Osteoporosis in Children and Adolescents

Craig B. Langman, MD, Head, Kidney Diseases, Children’s Memorial Hospital, Professor, Feinburg School of Medicine, Northwestern University
and Kelly A. Trippe, MA, Managing Editor, Osteoporosis Clinical Updates.

 

Editor's Introduction

It is only recently that the medical and research communities have arrived at something of a consensus regarding the definition of osteoporosis in children. In the past, osteoporosis was considered a disease of the elderly and/or adults with specific diseases that cause progressive bone loss and fragility fractures.

Supported by research conducted in past decade, pediatric osteoporosis has come to be defined as a disease of children and adolescents who have low bone density for their age, gender, race, and body size, coupled with a history of clinically significant fragility fracture. While osteoporosis in children is not linked to increased mortality as in adults, it may have tragic affects on a child’s quality of life, resulting in pain, loss of function, and other serious, long-term consequences. This article will discuss the pathway for development of healthy bone in children and touch on many of the disorders and treatments that can contribute to insufficient bone mass acquisition, low bone density, and/or increased fracture risk. We will also discuss pitfalls in the assessment of bone density and turnover in children. At present, there is no FDA-approved therapy for pediatric osteoporosis. Further research is needed to refine evidence-based recommendations for diagnosis and treatment of this disorder in children and adolescents. – Angelo Licata, MD, PhD

 

Bone Through the Life Cycle

In children, bone growth (modeling) takes place at two sites: inside the bone (at trabecular, endocortical, and intracortical surfaces), making it denser, and outside the bone, making it longer (at growth plates) or wider (at periosteum). Bone remodeling, the linked processes of resorbing old bone and forming new bone, takes place inside the bone on the trabecular surface. In the remodeling process, bone density increases when bone formation outpaces bone resorption. In children, bone modeling is the primary determinant of bone strength, rather than remodeling, as it is in adults.

Bone modeling begins during early fetal life and continues into infancy and childhood through adolescence. The skeleton continues to increase in density by remodeling well into the early third decade of life, even after cessation of linear growth.1 There then occurs a period of relatively stable bone mass (balanced remodeling) which has been termed peak bone mass. This is followed by a decline in bone mass that is characterized by elevated remodeling followed by higher rates of resorption than formation. In women this decline in bone mass is influenced by menopausal changes and in both genders it is a function of advancing age.

It appears that attainment of peak bone mass is under strong genetic influence. Based on studies in mono- and di-zygotic twins, it is believed that genetic variation may account for up to 80% of achieved peak bone mass.^[1] All of the genes responsible for peak bone mass are not known at this time. It is likely that a polygenic array is responsible. However, this also allows for a substantial influence, perhaps 20% or more, from environmental factors such as nutrition, exercise, and disease. Bone density begins to differ between individuals as early as infancy or early childhood and tracks thereafter according to the influence of hereditable and environmental factors.^[2] Pubertal gain in bone mass represents the next largest percentage increase after that seen in the first year of life and may respond to different sets of genes, but similar environmental stressors, than prior to puberty.

Approximately 60% of the variable risk of osteoporosis in adulthood can be ascribed to the magnitude of peak bone mass reached by early adulthood. The remaining 40% of the risk is explained by subsequent bone loss. Genetic factors, nutrition, hormonal disorders, medications, immobilization, and chronic illness during childhood and adolescence can limit attainment of optimal bone size, quality, mineral content, and density.

The sensitivity of the developing skeleton to nutrition and exercise is still unknown, but extreme deprivation of protein, vitamin D, and minerals is known to reduce bone density and/or quality. Similarly, the absence of weight-bearing exercise increases bone resorption and leads to a consequent reduction in bone mass. Failure to achieve a normal peak bone density will increase the lifetime risk of osteoporotic fracture. In severely affected children, low-impact (fragility) fractures may begin in childhood, resulting in skeletal pain and bone deformities.

 

Conditions Associated with Compromised Bone Growth and Mineralization in Children

Osteoporosis in children is most commonly observed clinically as a secondary feature of chronic disease and/or treatment for a chronic condition. Primary disorders, such as idiopathic juvenile osteoporosis and osteogenesis imperfecta, are less common but may have unique presentations that allow for their diagnosis. The following are brief, alphabetical descriptions of causes of osteoporosis in the pediatric population.

 

Common Pediatric Disorders that Can Lead to Osteoporosis

Anorexia Nervosa/Female Athlete Triad. Anorexia nervosa and female athlete triad are two syndromes seen in female adolescents that significantly compromise the attainment of peak bone density. Anorexia nervosa is characterized by malnutrition, low BMI, and low estrogen levels that frequently lead to amenorrhea. Each of these factors individually can increase the risk for osteoporosis; when combined, they are a potent threat to bone health both now and into the adult years. Studies demonstrate that low bone density persists in some young women who recover from anorexia nervosa, even after they have regained normal weight, eating habits, and hormonal status.^[3] Such considerations equally apply to female athletes who experience amenorrhea due to low BMI and excessive exercise (female athlete triad).

A second skeletal effect of anorexia nervosa is short stature. Research has shown this effect to be particularly pronounced in boys, possibly due to the fact that girls may have reached their terminal height by adolescent onset of anorexia, while boys have not, and so display the impact of low levels of insulin-like growth factor-1 (IGF-1) levels from persistent undernutrition.^{[3, 4]} In girls, research is currently investigating the role of appetite-regulating peptides, IGF-1, and cortisol levels in predicting which patients will experience the best bone outcomes from treatment for anorexia nervosa.^[5]

Asthma. Glucocorticoids (GCs) have long been used to control asthma in adults and children. Changes to bone density associated with prolonged use (over three months) of oral GCs in children are well documented. As a result, short-term oral GCs or inhaled GCs have traditionally been favored. Much is still unknown about the long-term bone effects of both short-burst oral and long-term inhaled GC use. Results of one large-scale study found dose-dependent declines in bone mineral acquisition and increased risk of osteopenia in boys on short-burst oral GC treatment but not in girls.^[6] The same study found that inhaled GC therapy was also associated with a small decrease in bone mineral accretion in boys and not in girls. One large population-based nested case-control analysis using UK data concluded that exposure to long-term inhaled GC use does not materially increase the risk of fracture in children and adolescents.^[7] In general, studies have not found significant adverse effects linked to long-term use of inhaled steroids at recommended doses in pediatric and adolescent populations; however, studies on effects in adulthood and old age are ongoing.^{[8, 9]} Since many patients on inhaled GCs may receive additional oral GCs, attention to bone density is suggested in this population during childhood and adolescence.

Chronic Liver and Chronic Kidney Diseases. Malabsorption of calcium and vitamin D, as well as impaired vitamin D 25-hydroxylation, are associated with most types of chronic liver disease (both cholestatic and non-cholestatic), contributing to bone loss and osteoporosis. As a result, secondary hyperparathyroidism is frequently a complication of chronic liver disease and has been termed hepatic osteodystrophy. Renal osteodystrophy occurs uniformly in progressive chronic kidney disease, and is part of the new entity, Chronic Kidney Disease-Mineral Bone Disorder (CKD-BMD).^[10]

In children with CKD-MBD, the kidneys fail to maintain adequate blood levels of calcium and phosphorus, leading to slowed bone growth and bone deformity. Common pediatric outcomes are short stature and bent long bones in the legs (renal rickets). CKD-MBD is present in almost every patient on dialysis and has been found in children with kidney disease even before they begin dialysis.^[10]

With successful organ transplantation of either the liver or kidney, other types of bone disease may arise that lead to insufficient bone density due to use of immunosuppressant drugs and GCs, as well as residual disease from past dialysis therapy in the case of CKD. Stunting of growth and limb deformations are common clinical findings in the pediatric population with CKD-MBD. Much is still unknown about alterations in bone metabolism caused by CKD-MBD and their effects on bone density in children. Routine screening by DXA is countermanded in recent guidelines.^[11]

Cystic Fibrosis. Reduced bone density is often observed in children and adults with cystic fibrosis. Contributing factors include poor nutrition, chronic infection, chronic inflammation, malabsorption of vitamin D and calcium, hypogonadism, delayed growth and maturation, and chronic use of intravenous or oral corticosteroids. (See discussion of asthma above). It is unclear if modern treatments for cystic fibrosis will reduce the alterations in bone density seen with earlier therapies.

Deprivational Rickets. A childhood disorder involving softening and weakening of the bones, deprivational rickets is primarily caused by lack of vitamin D, calcium, or phosphate due to poor nutrition or malabsorption syndromes such as celiac disease. Additonal forms of rickets result from hereditary factors that do not allow normal vitamin D processing in the liver or kidneys or from acquired chronic liver or kidney diseases. The hallmark of deprivational rickets is a reduction in circulating levels of 25-hydroxyvitamin D to levels below 10-15 ng/mL.

Vitamin D deficiency rickets is being recognized with increased frequency in the US and other western nations, particularly among breastfed babies, children with dark skin, and subjects with unusual diets (e.g., vegans) or insufficient sunlight exposure. In one study of US urban adolescents, 24% of the 300-plus subjects had significant vitamin D insufficiency (level of 25-hydroxyvitamin D < 30 ng/mL). Season, ethnicity, milk and juice consumption, body mass index, and physical activity were independent predictors of vitamin D deficiency. The prevalence was highest in African American teenagers and during winter, although vitamin D deficiency was found across all seasons and ethnicities.^[12] In research on children with primary and secondary osteopenia or osteoporosis, researchers observed a very high level of vitamin D insufficiency (80%), pointing to the importance of monitoring and supplementing vitamin D in pediatric patients with osteopenia and osteoposis.^[13]

Rickets is most likely to occur during active growth spurts, when requirements for calcium and phosphate are elevated. Uncommon in newborns, deprivational rickets may be seen in children as young as six months of age. The most significant risk factor for nutritional rickets in young children is unsupplemented breastfeeding for more than six months. The American Academy of Pediatrics recommends administration of 200 IU vitamin D per day to all breastfed infants after four to six weeks of age. The Institute of Medicine has recently undertaken a reassessment of the vitamin D requirements for the United States population.

Vitamin D deficiency rickets is easily treated by supplementation with calcium and vitamin D. If rickets is not corrected while a child is still growing, skeletal deformities and short stature may be permanent. If corrected while the child is young, skeletal deformities often diminish or disappear over time.

Diabetes. The growing prevalence of obesity and type 2 diabetes among US children and adolescents is an alarming public health trend. Its long-term consequences for bone health are worrisome. Type 2 Diabetes, occurring as a central feature of the metabolic syndrome, demonstrates variable effects on bone loss in adults, depending on the study cited. Current research suggests that obesity does not protect against fracture as previously believed and may instead increase fracture risk. Research is needed to understand the underlying mechanisms and fracture outcomes for children and adolescents.

Adults with type 1 diabetes have been shown in research to have both reduced BMD and increased fracture rates.^[14] Adolescents with type 1 diabetes have consistently been found to have lower bone density than size- and Tanner-stage-matched nondiabetic control subjects even when well controlled.^[15] It is suspected that metabolic effects of poor glycemic control lead to increased bone resorption and bone loss in young adults, as well as growth retardation. A long-term consequence of this altered bone mineral acquisition in adolescents may be to limit peak bone mass acquisition and increase the risk of osteoporosis in later life.^[16]

Endocrine Disorders. Bone growth and mineralization are in large part meditated by coordination of multiple endocrine processes. As a result, imbalances in any number of hormones can lead to disorders in bone resorption and formation. Severe hyperthyroidism, primary hyperparathyroidism (rare), and hyperparathyroidism secondary to chronic kidney disease or extreme vitamin D deficiency all can cause low bone density in children. Growth hormone insufficiency has been observed to negatively affect bone mineral density in both children and adults. Growth hormone replacement therapy has been shown to increase BMD in some studies; however, its effect on fracture risk is not fully understood.^[17] Sex steroid deficiency is also associated with impaired bone acquisition and lower bone mineral density.

GI Disorders. Celiac disease in children is more prevalent than previously believed.^[18] It occurs most often in females, in children with type 1 diabetes mellitus, and in children with Down syndrome. Screening patients with type 1 diabetes for celiac disease is advisable, even in the absence of clinical symptoms.^{[19, 20]} Celiac disease can lead to many serious medical conditions, including low peak bone density and early-onset osteoporosis due to malabsorption of calcium and vitamin D. Adherence to a gluten-free diet usually restores normal calcium absorption and bone density.

About 25% of patients with the inflammatory bowel diseases (IBD) Crohn disease or ulcerative colitis present before the age of 18^[21]. Both Crohn disease and ulcerative colitis affect bone negatively due to multiple factors, chiefly inflammation, but also malnutrition, growth failure, delayed puberty, and chronic GC use. In children, Crohn disease can delay sexual maturation and result in permanent stunting of adult height. Frequently, one of the first symptoms of IBD in a child is a fracture. ^{[22, 23]} To avoid these complications, it is important to control the inflammatory activity of the disease, while using GCs judiciously, and to ensure optimal nutrition. It is not clear that bone density is restored to normal with disease remission.^[24]

Organ Transplantation. Children who receive a solid organ transplant (bowel, heart, kidney, liver, lung) share many of the risk factors known to harm bone health in children who have undergone cancer treatment: radiation, poor nutrition, and bone-toxic pharmacologic agents. Added to these is the use of immunosuppressant agents post-transplant that also may adversely affect bone density.

Neoplastic Diseases. About one-third of childhood cancers are leukemias. The most common type of leukemia in children is acute lymphoblastic leukemia. Solid tumors occur as well, with brain tumors (e.g., gliomas and medulloblastomas) far more common than other solid tumors (e.g., neuroblastomas, Wilms’ tumors, and sarcomas such as rhabdomyosarcoma).

As a benefit of medical advances, more children survive childhood cancers and live longer. However, the chemotherapy (especially methotrexate), radiation, and high-dose GC treatments that are responsible for increased survival rates also contribute to increased risk of low bone density and consequent fractures. In addition to cancer treatments, immobility, underlying disease processes, and poor nutrition impair bone development and/or mineralization.^[25]

Neuromuscular Diseases. Spina bifida, cerebral palsy, paralysis, muscular dystrophies, and other neuromuscular disorders that restrict movement, mobility, and weight bearing affect bone density by both reducing (or curtailing) the mechanical stressors that stimulate bone formation and by increasing the rate of bone resorption. Factors commonly associated with neuromuscular diseases further reduce bone density: low body weight, nutritional inadequacy caused by feeding difficulties, and the use of anticonvulsants.^[26] Researchers have observed that physical therapy employing skeletal loading using controlled weight bearing either alone or with vibration platforms can result in increased bone mass in children with restricted mobility.^{[27, 28]}

Rheumatic Diseases. Children with chronic rheumatic conditions (rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, systemic lupus erythematosus, ankylosing spondylitis, juvenile dermatomyositis) are at increased risk for fractures, decreased bone mass, and osteoporosis as adults. Risk factors include the effects of chronic inflammation, poor nutrition, low calcium intake, lack of weight-bearing exercise, and long-term systemic GC therapy. Data from a recent study in Canada found significant indications of low bone mass (vertebral fractures) in children diagnosed with rheumatic disease even before they began GC therapy.^[29] Clinicians treating children with rheumatic conditions need to be aware of their patients’ increased risk for fracture before and after initiation of GC treatment.

Seizure Disorders. Many medications that are used to control seizure disorders have been shown to cause bone loss. This is especially true of drugs that stimulate the hepatic cytochrome P450 enzyme system, which converts vitamin D to its liver-produced metabolite (25-hydroxyvitamin D). Patients who use phenytoin, tegretol, or phenobarbitol or who are homebound or institutionalized are at particularly increased risk of vitamin D deficiency. Clearly, other factors contribute to bone loss, as vitamin D deficiency does not occur in all seizure patients. Patients may develop rickets, osteomalacia, or anticonvulsant osteopathy, which is characterized by low bone density and high bone turnover.

Sickle Cell Disease. Children with sickle cell disease have significantly reduced bone mineral content as compared with control subjects, adjusted for age, height, pubertal status, and lean mass. This puts them at risk for suboptimal bone density and future fragility fracture.^[30] Similar reductions in bone density occur in children and adults with other chronic anemias or bone marrow disorders such as Gaucher disease and thalassemias. Repeated sickling crises affect the strength of bone and may contribute to these fractures.

 

Uncommon and Rare Pediatric Disorders that Can Lead to Osteoporosis

Chondrodysplasias. The chondrodysplasias are a group of rare genetic disorders of collagen at the growth plates that cause skeletal deformity and short stature (dwarfism). There are several types of chondrodysplasias, each with its particular skeletal profile, severity, and prognosis. Skeletal deformities associated with defects of collagen can lead to fracture.^[31]

Cushing Syndrome. Cushing syndrome is caused by overproduction of cortisol due to adrenal, pituitary, or ectopic ACTH-producing tumors. The symptoms of Cushing syndrome may also occur with long-term high-dose GC therapy.

Growth failure and delayed puberty occur in children and adolescents with Cushing, leading to reduced terminal height and peak bone mass.^[32] It has been estimated that up to 70% of Cushing patients experience vertebral fractures and approximately 50% have osteoporosis. Reducing GC use and implementing bisphosphonate use has been shown to be more effective in improving bone mass than reducing serum cortisol levels alone. This may prove useful in patients with persistent postsurgical hypercortisolism to prevent further bone loss. ^[34]

Ehlers-Danlos Syndrome. Ehlers-Danlos syndrome is an increasingly recognized group of inherited disorders that affect collagen production. Defects in collagen weaken connective tissue in the skin, bones, blood vessels, and organs, resulting in the features of the disorder, which vary from mildly loose joints to life-threatening vascular complications. Fractures are often seen in patients with Ehlers-Danlos syndrome.^[33]

Extensive Burns. It is well established that severe burn injury in children is associated with low bone formation and long-term bone loss. Reasons for this stem from increased circulation of endogenous corticosteroids, chronic inflammation, vitamin D deficiency, immobilization, and hypercalciuria secondary to hypoparathyroidism. Maintenance of bone mass in pediatric burn patients has proved so far to be very tricky. Efforts involving vitamin D supplementation have failed to show improvement in either serum vitamin D levels or bone density, as has short-term treatment with recombinant human growth hormone.^{[34, 35]} Early treatment with the IV bisphosphonate, pamidronate, has shown promise in maintaining bone mass in pediatric burn patients over two years, although much research remains to be done before the best approach to treatment can be established. ^{[36, 39]}

Gaucher Disease. Gaucher disease is an inherited metabolic disorder characterized by the accumulation of glucocerebroside in the spleen, liver, lungs, bone marrow, and sometimes in the brain, causing damage to these organs. Pharmacological enzyme-replacement therapy is available, but the consequences of Gaucher disease in bone (including fracture) seem to continue after treatment. There are a few reports of the successful use of bisphosphonates for this condition.

Hypophosphatasia. Hypophosphatasia is a rare genetic disease characterized by deficiency of tissue-nonspecific alkaline phosphatase (TNSALP) activity, excessive urinary excretion of phosphoethanolamine, poor bone mineralization, and skeletal anomalies. The shortage of alkaline phosphatase (ALP) alters the process of skeletal mineralization, causing reduced transformation of phosphoethanolamine into phosphatidylethanolamine (cerebral phospholipid) with consequent high serum and urinary levels of phosphoethanolamine, a sensitive and highly specific marker for the disease. Four clinical forms have been described, based on the age of onset, with different courses and prognoses.

Hypophosphatasia may resemble a rachitic disease or osteogenesis imperfecta, but unlike those conditions it is not responsive to vitamin D therapy. Children who present with rickets and premature loss of deciduous teeth should be tested for reduced serum alkaline phosphatase activity.^[37] Interestingly, as a secondary phenomenon, excess production of prostaglandins has been associated with this condition. The bone pain encountered by patients is quite responsive to oral, non-steroidal anti-inflammatory drugs (NSAIDs).^[38] Children with hypophosphatasia should be monitored for kidney damage if NSAIDs are used chronically. Recently, recombinant human alkaline phosphatase has been used in experimental models and adults with hypophosphatasia for repair of bone abnormalities.^[39] Several potential therapeutic approaches under investigation show early promise in children including enzyme replacement and transplantation of donor bone fragments and marrow.^{[40, 41]}

Idiopathic Juvenile Osteoporosis. Idiopathic juvenile osteoporosis (IJO) is a rare disease that typically occurs in otherwise healthy children. The average age of onset is 7 years, with a wide range reported from ages 1 to 13 and older. Most common complaints on presentation are gait difficulties and pain in ankles, heels, or lower back. The skeletons of children with IJO show reduced bone density with a resulting increase in the risk of fractures of the weight-bearing bones (particularly in the metaphyses) and spine, with collapsed or misshapen vertebrae. Early diagnosis of IJO is important so that steps can be taken to protect the child’s spine and other bones from fracture until remission occurs.

Most children with IJO experience a complete recovery, although spinal scoliosis or kyphosis may persist. Growth may be somewhat impaired during the acute phase of the disorder. However, upon recovery normal growth resumes and catch-up growth often occurs. Bisphosphonates have been given to some children with IJO in a research environment. The disorder seems to arise from a reduction in osteoblastic activity with impaired bone modeling that, upon recovery, shows catch-up activity. However, the disorder remains poorly understood at present, and we remain uncertain as to its long-term consequences for bone health.

Klinefelter and Turner Syndromes. Both Klinefelter and Turner syndromes are associated with hypogonadism and delayed maturation due to genetic abnormalities that impair the function of testis and ovaries, respectively. Low bone mineral content is common and is particularly severe in patients who are not treated adequately with sex hormone replacement therapy. The genetic defects in both syndromes may also contribute to variable degrees of low bone density that is unrelated to low circulating levels of sex hormones. Increased fracture rates in untreated patients have been documented.^{[42, 43]}

Bisphosphonates have been shown to increase bone density in adult Klinefelter patients.^[44] In patients with Turner syndrome, a combination of growth hormone and estrogen replacement therapy been shown to be effective in improving height and bone mass in adolescent patients.^[45]

Osteogenesis Imperfecta. Osteogenesis imperfecta (OI) is a genetic disorder in which defective collagen causes bones to be qualitatively abnormal, less dense, and easily broken. At least seven types of OI have been identified. While the characteristics of each type of osteogenesis imperfecta can vary greatly from person to person, consistent among all types of OI is the tendency for patients to develop low bone density and fractures. For this reason, osteoporosis is an almost universal consequence of osteogenesis imperfecta. In most studies of children with OI, oral or intravenous bisphosphonates have been shown to reduce fractures, ameliorate pain, and improve growth.^{[46, 47]} These benefits appear to be realized in the first two to four years of treatment, and long-term effects are not yet fully characterized.^[48]

Osteoporosis Pseudoglioma Syndrome. Osteoporosis pseudoglioma syndrome is an autosomal recessive disorder caused by inactivating mutations in the gene that encodes low-density lipoprotein receptor-related protein-5 (LRP-5). Osteoporosis pseudoglioma syndrome is characterized by severe juvenile-onset osteoporosis, congenital or juvenile-onset blindness, short stature, and skeletal deformity due to multiple fractures. Small uncontrolled studies have found intravenous bisphosphonate therapy to be beneficial in patients with this condition and suggested that it may prevent progressive vertebral deformity.^[49]

Techniques for Assessing Bone Density in Children

In growing children, the skeleton experiences modeling and remodeling. In modeling, endosteal resorption and periosteal new bone formation occur on distinct bone surfaces. In remodeling, osteoclastic-mediated bone resorption is followed by osteoblast-directed bone formation on the same bone surface.^[50]

Techniques to measure BMD, such as DXA, assess specific sites, such as the spine and portions of the hip. In children, bone modeling occurs at many sites not measured by such technology. Alterations in modeling, rather than remodeling, may account for insufficient bone mass accretion. As a result, assessment of both trabecular and cortical bone compartments is critical for understanding the totality of bone dynamics and osteoporosis in children but is not as important in adults, where alterations in trabecular bone seem sufficient for diagnosis and therapy of osteoporosis.

Several technologies are used to assess bone in children: dual-x-ray absorptiometry, conventional x-ray, QCT, pQCT, and ultrasound.

Dual x-ray absorptiometry (DXA). Dual-x-ray absorptiometry (DXA), while far from perfect, is currently the best option for diagnosing osteoporosis in children and adolescents in the clinical setting. Its ready availability has led to the often indiscriminate use of this technique to measure bone density in children, with inconsistent results. Research has observed that use of DXA on children can lead to significant overdiagnosis of osteoporosis due to misinterpretation of findings.^[51]

One potential cause of misdiagnosis is the use of the T-score to interpret DXA findings rather than the Z-score. The T-score compares DXA measures to a standard adult reference point, while the Z-score compares the DXA outcome to an age-matched reference point. To improve the utility of DXA, researchers have developed reference curves for bone density adjusted for chronologic age, gender, ethnicity, height, pubertal status, and weight. Unfortunately, such programs are limited by the size of their databases as well as their applicability only to users of the same DXA equipment, software version, and technique.^{[52, 53]} While data indicate that there is an inverse relationship between pediatric bone fragility and fracture risk, the exact nature of this relationship and how best to identify actual bone strength in children is not yet clearly characterized.

DXA can be used to formulate a variety of bone density measurements at a variety of sites: bone area (BA), bone mineral content (BMC), bone mineral density (BMD), bone mineral apparent density (BMAD – also called volumetric BMD), and BMC/lean mass (BMCLM), measured at the spine, hip, wrist, total body, or total body less the head (TBLH). Which type of measurement at which site is most predictive of future fracture risk in children? The jury is still out.

Data from a retrospective case-controlled study of over 300 children looking at the various DXA measurement types and sites observed that low spine BMD and BMAD were significantly associated with increased upper limb fracture risk in children, while lower spine and hip BMAD were associated with higher risk of wrist and forearm fracture.^[56] The study did not find significant links between fracture risk and BA or BMCLM and found inconsistent associations between fracture risk and BMC or measurement at other BMD sites.^[54] A much larger study also observed that BMAD, calculated to adjust BMC for bone area, height, and weight, significantly predicted future fracture risk, while BMD did not.

It is likely that BMD alone does not fully account for fracture risk. As in adults, bone size, bone quality, bone turnover, and trauma are also likely to be important contributors to the risk of fracture. In children, the situation is made more complex by the physiology of growing bone.^[55]

As a result, low bone density by DXA alone is not sufficient for a diagnosis of osteoporosis in a child. The presence of both pathological fracture and low bone density by DXA measurement (Z-score of ≤ -2) is considered necessary to diagnose osteoporosis in pediatric and adolescent patients.^[58] Pathological fractures are defined as vertebral compression fracture, single fracture of lower extremity long bones, or two or more fractures of upper extremity long bones in the absence of explainable significant trauma (such as a motor vehicle accident).^[56]

X-ray. Plain radiography is an inexact method to determine bone density, since it is influenced greatly by technique, radiation exposure, and its inherent non-quantitative basis. However, it is an excellent tool to demonstrate rickets, fractures, and deformities in children. Lateral radiographs of the spine are valuable for detecting vertebral compression fractures, which are very common in children with chronic diseases that result in bone loss and osteoporosis.^{[57, 58]} Semi- or full quantitative techniques have been derived for plain radiography of bone in children to determine some aspects of bone density.^[59] In general, these have been applied in only a few centers or in specific studies and are not widely available to clinicians or for the overwhelming majority of patients.

QCT and pQCT. Quantitative computed tomography can assess volumetric bone density with adequate separation of cortical and trabecular compartments, giving it significant theoretical advantages over DXA in assessing the bone health of children.^[60] However, there are marked drawbacks including high cost, lack of widespread access, and relatively high radiation doses. QCT is currently a valuable research tool. A variety of machines now use this technology to measure bone density in peripheral bone sites (pQCT), which may facilitate wider clinical application in the future. At present, the technique remains accessible only in the research environment.^[61]

Ultrasound. Ultrasound has been used to measure bone mass and to assess indices of bone strength in adults and children.^[62] Because of the large variation in bone size among growing children, ultrasound techniques are currently used only for research, but show promise for future use in children.

 

Treatment of Osteoporosis in Children

In children and adolescents, safe and effective doses have not been established for the many drugs used to prevent and treat osteoporosis in adults. These agents include bisphosphonates, teriparatide, calcitonin, denosumab, and activated forms of vitamin D. The routine use of these agents in children is strongly discouraged. Further research is needed to establish appropriate dosing, duration, and management — or whether they can safely be used at all. Much is still unknown about potential toxicities that may occur due to differences between children and adults in skeletal modeling/remodeling, pharmacokinetics, and/or pharmacodynamics.^[63]

Several oral and parenteral bisphosphonates are currently under investigation for use in pediatric and adolescent patients. While short-term safety and efficacy data (three-year) have been promising, the use of these drugs remains controversial due to the lack of data regarding their long-term effects on the developing skeleton. In addition, although trials have shown increases in BMC and BMD in chronically ill children on IV bisphosphonates, they have not established a correlation between this gain and reduction in fragility fracture or improved quality of life.^{[64, 65, 66]} There are additional concerns regarding the use of bisphosphonates in young females who may become pregnant, because release of accumulated bisphosphonate from the mother’s skeleton poses a theoretical risk to developing fetal bones.

Generally accepted therapy for osteoporosis in children begins with identifying and treating underlying causes and addressing any correctable abnormalities. This should be coupled with appropriate weight-bearing exercise and optimized nutrition, with particular attention to achieving recommended daily intakes for calcium and vitamin D. For children who fail to respond to these measures and continue to experience recurrent fragility fractures, vertebral collapse fractures, and low bone density (Z-score), pharmacologic therapy may be a reasonable consideration under the auspices of specialists who have experience using investigational or experimental agents.

Children with fracturing osteogenesis imperfecta frequently benefit from conservative bisphosphonate therapy, in part due to pain reduction. Children suffering from pathologic fractures caused by other chronic conditions should receive bisphosphonate treatment only as part of a clinical trial or in the hands of an expert practitioner.