Update on Pediatric Bone Health

Chronic Illness

Chronic systemic illnesses can be detrimental to the growing skeleton. Chronic renal insufficiency leads to abnormal bone metabolism via disturbances in calcium and phosphate handling, altered vitamin D and PTH levels and function, and altered renal clearance of aluminum and other metabolites. Additional factors include malnutrition, metabolic acidosis, and anemia.¹⁹

Gastrointestinal disorders such as celiac disease and inflammatory bowel disease (eg, Crohn disease, ulcerative colitis) interfere with calcium absorption from the gut and cause vitamin D insufficiency or deficiency.

Liver dysfunction may impair bone health through calcium and vitamin malabsorption, failure of vitamin D activation, bile salt deficiency, and chronic malnutrition.²⁰

The risk for low BMD in individuals with cystic fibrosis is multifactoral and includes reduced gastrointestinal absorption of calcium and vitamin D, reduced testosterone levels, chronic hypoxia, prolonged steroid use, and reduced lean tissue mass.²¹ Chronic hypoxia and decreased physical activity in patients with asthma may inhibit normal bone metabolism.

Endocrine system disorders that result in inadequate or excessive levels of systemic hormones can negatively impact bone health. For example, growth hormone deficiency, diabetes mellitus, and hyperthyroidism are all risk factors for osteoporosis.^22-24 Pubertal hormones, especially estrogen, play a critical role in bone mass acquisition. Because the majority of BMD is accrued during the peripubertal years, recognition and timely treatment of hypogonadism are key.

Decreased muscle development and impaired ambulation in children with cerebral palsy and muscular dystrophy contribute to increased risk of osteoporosis.²⁵

Primary Bone Disease

Osteogenesis imperfecta includes a spectrum of genetic disorders of collagen synthesis resulting in abnormal skeletal and connective tissues. Type III osteogenesis imperfecta is a severe form of the disease and is easy to identify because it is associated with obvious bony deformities and reduced BMD. Type II is lethal in the perinatal period. Although types I and IV are milder and less easily recognized, they should be considered in the differential diagnosis of children with multiple fractures.

Current Medication and Treatments

Glucocorticoids are well known for their potent anti-inflammatory effects in patients with chronic inflammatory disorders such as ulcerative colitis and cystic fibrosis. One adverse effect of glucocorticoid use is its detrimental impact on BMD. At pharmacologic doses, glucocorticoids impair the function and reduce the life of osteoblasts.²⁶ Simultaneously, glucocorticoids accelerate the maturation and activity of osteoclasts while exerting antiapoptotic effects on these cells.²⁷

In addition, glucocorticoids reduce intestinal calcium absorption and promote renal calcium excretion. The resulting increase in PTH secretion and reduced levels of sex steroids caused by chronic glucocorticoid therapy promote bone resorption. Therefore, the combination of impaired bone formation and accelerated bone resorption increases risk of osteopenia or osteoporosis.

Low BMD resulting from anti-epileptic medication is multifactoral. Such medication can accelerate vitamin D metabolism in the liver and lead to a deficiency of this nutrient. Low BMD is also induced by the direct effects of anti-epileptic drugs on bone cells, resistance to PTH, inhibition of calcitonin secretion, and impaired calcium absorption.^28,29

Patients with seizure disorders who require combination therapy and may be taking more than one anti-epileptic agent at a time are at an even greater risk. In children with cerebral palsy who have decreased lean muscle mass and limited weight-bearing activities, anti-epileptic agents compound the risk for low BMD.

As the number of survivors of childhood cancer increases, the toxic effects of chemotherapy and radiation on the skeleton are becoming more apparent. Osteoporosis is one of many health issues in a long list of potential “late effects” caused by these therapies.^4,30 Therefore, physicians must provide appropriate surveillance.

Nutrition

Most adolescent females consume less than half of the recommended daily allowance of calcium.³¹ Milk provides a substantial amount of calcium per serving, yet milk consumption has decreased while soft drink consumption has increased.³² Flavored water is another popular choice and is healthier than soft drinks, but it lacks important nutrients found only in milk.

For example, milk is a good source of protein and contains multiple vitamins and minerals (eg, iron, magnesium, phosphorus, potassium, zinc) crucial for developing healthy bones. The vitamin K found in milk is a cofactor for osteocalcin synthesis and the vitamin D used to fortify milk augments calcium absorption from the intestine.

In addition, specific components of milk directly promote bone formation and inhibit bone resorption. For example, lactoferrin stimulates osteoblasts and inhibits osteoclasts, resulting in an overall increase in bone mass.³³ Other dairy products such as lowfat yogurt and cheese are also very nutritious and help boost dietary calcium intake.

Adolescents with severe malnutrition, such as those with anorexia nervosa, are at risk for developing osteopenia or osteoporosis caused by inadequate nutrition and, in women, estrogen deficiency.³

In female adolescents, physicians should be aware of the “female athlete triad”—anorexia, amenorrhea, and osteoporosis—which can have a negative effect on overall health and athletic performance.^5,6 Whereas exercise is generally anabolic for bones, the excessive exercise typical for these young women may exacerbate the insult to their bones.

Conversely, the obesity epidemic among our nation's youth is staggering. Although the 9 million overweight or obese children in the United States do not meet the classic definition of malnutrition, most are, in fact, undernourished in the sense that their diets are generally poor and lack many important nutrients.³²

In addition, obesity itself is a risk factor for fracture in children.³⁴ Although it seems counterintuitive, the data are convincing. Obese children are generally sedentary, causing poor musculoskeletal coordination and inadequate lean muscle mass to control their body mass. Because their bone development does not keep pace with their weight gain, their relatively immature skeletons must bear a disproportionate amount of weight when they fall and can result in fracture.³⁴

Lifestyle

According to 2005 data, approximately 43% of US high school students consume alcohol,³⁵ while 4.5 million US adolescents smoke cigarettes.³⁶ Such lifestyle habits, as well as lack of physical activity, can all contribute to poor bone health.

For example, chronic excessive consumption of alcohol is toxic to osteoblasts and results in impaired bone formation.^37,38 Cigarette smoking can lead to bone resorption through alterations in calcium and vitamin D metabolism and perturbations in the vitamin D–PTH axis.³⁹

Sedentary individuals not only lack the important bone-building stimulus of exercise in their daily lives but also are more likely to be overweight and perhaps not as focused on good nutrition, all of which augment their risk for poor bone health.

Diet

Patients should be encouraged to follow a well-balanced diet that includes sufficient calories, protein, and healthy fats as well as adequate amounts of calcium and vitamin D. Figure 3 lists some common foods that are rich in calcium.⁴⁷ Additional information, including recommended daily allowances per age group and a complete list of foods rich in calcium, is available at http://dietary-supplements.info.nih.gov/factsheets/calcium.asp.⁴⁷ A good rule of thumb is to recommend 3 to 5 servings of lowfat dairy foods per day.^48,49

As previously described, vitamin D is essential in calcium absorption. Until recently, the American Academy of Pediatrics recommended 200 IU per day of vitamin D,⁵⁰ but many experts in pediatric bone disease believed that this amount was not enough. In a November 2008 report, the American Academy of Pediatrics⁵¹ revised their recommendation to 400 IU per day of vitamin D. However, it has been suggested that 800 to 1000 IU/day is needed to maintain a serum 25-hyroxyvitamin D level at or above 30 ng/mL, which is becoming more widely accepted by pediatric bone experts as the optimal level of vitamin D in the bloodstream.⁵²

Figure 3.

Selected foods by calcium content. Source: Dietary supplement fact sheet. ⁴⁶

Although increased calcium and vitamin D intake is primarily a preventative measure, it also serves as a treatment model for some patients and may improve BMD.

Exercise and Lifestyle Habits

Regularly engaging in weight-bearing exercise and maintaining a healthy weight are essential for bone health. Weight-bearing exercise, including activities that involve walking, running, and jumping, is best. Many young children do these things naturally, but older children and adolescents may need encouragement. Exercising as a family or in another group setting (eg, friend, class, team sports) may help children and young adults maintain motivation and consistency.

For those unable to bear weight or engage in exercise, vibration therapy may be an option for optimizing bone health.^53,54

In addition, all patients should be educated about the importance of avoiding unhealthy habits like cigarette smoking and drinking alcohol in excess. Physicians should convey that in addition to the increased risk of heart disease, stroke, cirrhosis, and more, cigarette smoking and alcohol consumption increase lifetime risk of low BMD.

Systemic Disease

It is important to identify any underlying systemic disease, such as those previously listed, that could contribute to low BMD. Various laboratory tests and measurements (Figure 4) can help clinicians screen for underlying liver and kidney function abnormalities, vitamin D deficiency or insufficiency, and celiac disease.

For example, strict adherence to a gluten-free diet in children with celiac disease can result in improved or normalized BMD after only 1 year of therapy.⁵⁵ The impact this improvement may have on helping a child attain peak BMD, however, is unknown.

For other chronic illnesses, achieving good control of the disease may not be sufficient to optimize skeletal health, but minimizing disease severity remains a crucial element of preventing and improving low BMD.

For adolescents with delayed puberty, gonadotropins (ie, luteinizing hormone, follicle-stimulating hormone) and evaluation of estrogen or testosterone levels might yield a diagnosis of hypogonadism. In such cases, administration of exogenous sex steroids may be necessary to attain peak bone mass.

Osteotoxic Medications

Every attempt should be made to minimize the insult to the skeleton caused by medications that are harmful to bones.

Many of the chronic illnesses that predispose patients to osteoporosis are characterized by inflammation that must be controlled by glucocorticoids. It is well known that inflammatory mediators, including cytokines such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor α, can have direct deleterious effects on the skeleton. Striking a balance between avoiding excessive doses of steroids and controlling inflammation, therefore, is a challenging task.⁵⁶ The same is true when using any medication known to have potentially detrimental effects on the skeleton to manage disease activity. Baseline and follow-up DXA scans every 6 months are recommended for children treated with glucocorticoids for more than 2 months.⁵⁷

Figure 4.

Screening studies to evaluate children suspected of having low bone mineral density. Abnormal laboratory results could identify problems with liver or kidney function, low levels of vitamin D, or celiac disease.

Pharmacologic Intervention

Bisphosphonates, also called diphosphonates, are anti resorptive agents that interfere with osteoclast-mediated bone resorption. By reducing the functional capacity of osteoclasts, these medications tip the balance between bone formation and resorption in favor of bone formation.

In pediatrics, these medications are generally reserved for patients with a chronic illness—such as cystic fibrosis, cerebral palsy, and osteogenesis imperfecta—that seriously impairs bone mineral accrual. Intravenous pamidronate, one of several bisphosphonates, has been most extensively studied in pediatric patients with osteogenesis imperfecta. It has been very effective in increasing BMD and reducing fracture rates, thereby improving quality of life.⁵⁸

Bisphosphonates have also been used in several other settings, such as low BMD associated with fractures caused by immobilization or prolonged glucocorticoid therapy.^59,60 Unfortunately, clinical trials^61-63 to date have generally included small numbers of study subjects, leaving many questions unanswered. For example, there are several protocols for administration of intravenous pamidronate,^64-66 but optimal dosing and therapy duration are not known.

Although excessive doses can lead to osteopetrosis,⁶⁷ in the short term, these medications appear to be safe when used at recommended dosages. However, certain adverse effects may still occur.

In our experience, intravenous bisphosphonates may cause flu-like symptoms, including fever and myalgia, that are most pronounced when treatment is initiated. Generally, these symptoms become much less severe or disappear after continued use. In addition, such symptoms are easily remedied by administration of analgesics or antipyretics.

Oral agents may lead to gastroesophageal reflux or esophagitis. Osteonecrosis of the jaw is a rare but severe and debilitating potential complication of bisphosphonate therapy that has been reported in some adults taking these medications. Many such cases followed dental trauma such as tooth extraction, but others occurred spontaneously.⁶⁸ Although no cases of osteonecrosis of the jaw have been documented in children to date,^69,70 physicians treating pediatric patients with bisphosphonates should be aware of this potential complication. Ideally, patients should have a thorough dental evaluation before beginning bisphosphonate therapy. Good oral hygiene and regular dental care are essential throughout treatment.

If bisphosphonate therapy is stopped before the completion of linear growth, the interface between treated bone and bone naïve to bisphosphonate therapy is prone to fracture.⁷¹ Because patients with different etiologies of low BMD will not have a uniform response to this therapy option, sustained effects of these medications will likely vary with underlying disease and disease severity.

Long-term data on fracture rates after bisphosphonate therapy are needed to determine if such treatment has a lasting impact on reducing morbidity associated with fragility fractures.⁷² For example, bisphosphonates remain in bone for years, but it is not currently known if these agents will lead to health hazards for patients or their offspring. As a result, bisphosphonates are currently not recommended for prevention of osteoporosis. Rather, their use is reserved for treating patients with severe debilitating bone disease, including low BMD associated with fractures and chronic bone pain.

Because these agents are not approved by the US Food and Drug Administration for use in children and adolescents, and given the paucity of long-term outcome data from bisphosphonate therapy, these agents should be used judiciously and should be prescribed only by physicians experienced in managing low BMD and metabolic bone disease in pediatric patients.