Bone disturbances in childhood:
The clinical utility of biochemical
and bone mass measurements

CRAIG B. LANGMAN, MD
RICHARD M. SHORE, MD

aSpring 1997

NOW THAT RESEARCHERS  and clinicians are gaining a better understanding of bone and mineral metabolism, they are realizing that disorders of the adult skeleton begin in childhood. Also becoming clearer is the fact that children manifest specific disturbances in the normal accumulation of bone mass in the context of diseases and their therapies. This article reviews recent developments in the ability to understand disturbances in mineral metabolism by sophisticated biochemical evaluation and by the measurement of bone mass.

What is bone?

Bone is a living, dynamic organ that serves protective, structural as well as metabolic functions. Its composition is related to the skeleton’s two principal functions: supporting the body and acting as a physiologic reservoir of ions. Bone is composed of 70% mineral and 30% organic constituents. Hydroxyapatite makes up 95% of the mineral portion. The organic component consists predominantly of type I collagen; non-collagenous proteins of importance include osteocalcin and transforming growth factor-ß. Cells occupy 2% of the organic matrix of bone and are responsible for formation, resorption and maintenance of the remodeling cycle. Osteoclasts arise from mononuclear cell precursors and resorb bone by both physicochemical and cellular processes; the polarity of their H⁺ -ATPases accomplish this task. Osteoblasts stem from primitive mesenchymal cells and are the cells that form and mineralize secreted bone matrix. Osteocytes differentiate from osteoblasts and maintain the nutrition of bone.

Bone can be divided into two anatomic types: cortical bone, the compact bone of the appendicular skeleton that provides tensile strength; and trabecular bone, the primary component of vertebral bodies of the axial skeleton and flat bones of the skull and pelvis that provide a greater surface area for calcium homeostasis. The ratio of cortical to trabecular bone differs in various parts of the skeleton, and both should be evaluated in studies of skeletal mass. Sites often measured include the distal one-third radius, which is 95% cortical and 5% trabecular; the distal one-tenth radius, 25% cortical and 75% trabecular; the lumbar vertebral bodies L₁–L₄, 5% cortical and 95% trabecular; the femoral neck, 75% cortical and 25% trabecular; and the greater trochanteric area of the femur, 50% cortical and 50% trabecular.

Bone mass accumulation: Peak bone mass

Bone mass accumulation is a major task accomplished during childhood and adolescence. The process is a dynamic one between forces that form bone and those that promote bone loss. Interestingly, both formation and resorption must be present for bone mass accumulation to proceed in a normal manner. Bone mass is accumulated progressively from infancy through young adulthood and generally parallels the linear growth curve. Thus, a large percent of total skeletal mass is achieved during the adolescent growth spurt—an increase of approximately 8% per year. The rate of increase in bone mineralization is much lower during the mid-childhood years compared to that seen in adolescence. Complete skeletal maturation is not reached, however, until the middle to latter part of the third decade of life. The achievement of final bone mass is termed peak bone mass. Peak bone mass is defined as the greatest amount achieved; bone mass declines thereafter with advancing age.

Many factors can impinge on normal peak bone mass accumulation. The most important is heredity (on an unknown genetic basis), which accounts for more than 70% of cases. Recent evidence in adults suggests that bone mass inheritance may be linked to, or associated with, polymorphisms in the gene for the vitamin D receptor although data remain controversial, and evidence is lacking in children. More interesting data suggest that the ability to increase bone mass in children by nutritional means may be linked to that same polymorphism.

The environment can exert modifying effects on normal bone mass accumulation as demonstrated, for example, by the effect of dietary calcium supplementation. Johnston et al observed the potential effects on skeletal bone mass of supplemental calcium citrate malate (1000 mg/day) in one randomly-chosen twin of 70 pairs of monozygotic twins treated for three years. In the treatment group, significant increments of cortical and trabecular bone at several measured sites were documented in the 22 prepubertal children who received calcium supplementation, but not in the 23 postpubertal or pubertal children. The study demonstrated clearly that calcium supplementation over and above the recommended dietary allowance in pre-pubertal children led to an enhanced rate of increase in bone mineral density (BMD) above a genetic threshold in the short-term. If the calcium supplementation continued, such an increase would lead to an elevated peak bone mass. However, once it was stopped, the bone mass reverted downwards to the level of the unsupplemented twin, suggesting no long-term effect on bone mass. In the study, the inability to document the effects of calcium supplementation to increase bone mass in the older children and adolescents may have been obscured by the otherwise rapid gain that normally occurs at this time in this group. Furthermore, studies in normal children, in general, have shown a strong positive relationship between physical activity and BMD, while extremes of exercise may exert a negative influence on bone mass accumulation.

Biochemical measurements of bone metabolism

Clinical assessment of bone metabolism begins by measuring the ions and major hormones involved in the process of bone mass accumulation. The reader is referred to a recent review of the contemporary measurements of calcium and phosphorus in blood and urine in relation to bone metabolism. Assays for the major calcium-regulating hormones include intact parathyroid hormone (iPTH), 25-OH vitamin D (25OHD), and 1,25(OH)₂ vitamin D (1,25(OH)2D).

Parathyroid hormone (PTH) responds to the immediate variations of the ionized calcium concentration of the blood. Hypocalcemia stimulates secretion and increased synthesis of PTH while hypercalcemia suppresses both. The immediate effect of an increase in circulating iPTH is to increase calcium egress from its skeletal reservoir through an indirect stimulation of osteoclastic osteolysis, thereby defending the reduction in blood ionized calcium. Additionally, the phasic release of iPTH under such circumstances leads to a stimulation of the synthesis of 1,25(OH)₂ D by activation of the renal 1–hydroxylase enzyme in proximal convoluted tubules. The consequent elevation in circulating levels of 1,25(OH)₂ D increases dietary calcium absorption from foodstuffs in the intestine, enhances the PTH-directed osteolysis that mobilizes calcium by increasing the differentiation of committed osteoclast-precursor cells to form active osteoclasts, and limits the response of secondary hyperparathyroidism through a genomic effect that decreases PTH mRNA transcription rates. Thus, long-term secondary hyperparathyroidism is associated with a reduction in bone mass by increasing bone resorption. However, cyclical administration of PTH is also trophic for bone, and studies in elderly men have demonstrated an increase in bone density under such administration.

The major storage form of vitamin D in the body occurs after the hepatic conversion of the parent compound into the 25(OH)D moiety, and the serum level of 25(OH)D serves as an index of vitamin D adequacy. Measurement of 25(OH)D must be carefully evaluated; serum levels can be altered by dietary intake of the parent compound, malnutrition, diseases that lead to fat malabsorption or a catabolic state, and the season of the year (sun exposure). The serum level of 1,25(OH)₂ cannot be indexed to another blood value of the mineral system; it is inversely related to the dietary intake of calcium. Disturbances of phosphate metabolism also inversely affect the serum levels of 1,25(OH)₂ D, while systemic acidosis decreases the hormone’s serum levels.

Recent advancements in the understanding of the biochemical and molecular processes of bone formation and bone resorption have led to the development of blood and urine markers of these processes. The normal values that have been established for each of these markers can help in the evaluation of children with suspected alterations in the normal dynamics of bone mass accumulation.

Measures of bone formation include bone-specific alkaline phosphatase (BsAP), a component of the plasma membrane of the osteoblast, which is released during osteoblastic activity. Osteocalcin (OC) or bone gla protein, derived from osteoblasts, is a vitamin K-dependent gamma carboxylated protein. Its serum concentration derives from newly synthesized protein that does not bind to the mineral phase of bone; its level in the blood correlates with rates of bone mineralization. Carboxy-terminal propeptide of type I procollagen (PICP) is also a marker of bone formation. Its serum concentration reflects the number of newly synthesized collagen fibrils released into the extracellular bone matrix.

Measuring bone resorption can be done by assessing the urinary concentration of the deoxypyridinoline crosslinked telopeptide domain of type I collagen, which represents hydroxylysyl and lysyl post-translational components of type I collagen crosslinkage that reflect the breakdown of mature collagen. Recently, the urinary excretion of N-linked telopeptides of the collagen molecule has been shown to be more specific than the crosslinked compounds for rates of bone resorption, and this value is measured now.

Thus with specific markers of formation and resorption, it is possible to profile the state of bone metabolism (Table 1). Under most circumstances, bone disease is associated with the change in these markers going in the same direction. This relationship occurs in early post-menopausal osteoporosis and in the bone disease associated with chronic kidney diseases, when the markers of both resorption and formation are above normal. The relationship also occurs during prolonged corticosteroid administration; in this situation, though, both sets of markers are often below normal.

However, it is dissociated bone disease that is so detrimental to integrity of the skeleton in children and may lead to significant inability to accumulate bone mass normally. This occurs in the osteopenia of juvenile rheumatoid arthritis, cystic fibrosis, systemic burns, and other chronic inflammatory diseases of childhood.

Radiologic techniques to measure bone mineral content and density

Given the clinical and biochemical picture that is relevant to suspected metabolic bone disease, the clinician must next determine the level of bone mass by quantitative means. There are many radiologic methods for evaluating bone mineral. Qualitative evaluation of skeletal radiographs is a very insensitive method because up to a 50% reduction of bone mineral may be needed before demineralization can be recognized. The appearance of bone mineralization is also highly dependent on radiographic technique. However, radiographs remain important in identifying specific bone disorders such as rickets and hyperparathyroidism.

Radiographs can also be evaluated quantitatively by measuring cortical thickness of bone. This is most often performed on the second metacarpal using a scaled magnifying glass, and normal values are available for children and adults of several ethnic groups. However, cortical thickness measurements are not adequate to follow changes in bone mineral status because they are not as accurate or precise as the techniques that measure photon absorption.

There are three major quantitative methods for assessing bone mass that are much more accurate than measuring cortical thickness. These methods measure the effect of bone mineral content (BMC) on the attenuation of a photon beam; they include single photon absorptiometry (SPA), dual x-ray absorptiometry (DXA), and quantitative computed tomography (QCT). SPA and DXA measure the BMC within the area being examined. The ratio of these defines bone mineral density (BMD) as an "areal density" (g/cm² ) rather than a true volumetric density. QCT, which is performed with a CT scanner, can measure volumetric bone density (g/cm³ ), and it can also evaluate pure trabecular bone in the spine without including the cortical component of the vertebrae. However, QCT is more costly than DXA, more difficult to schedule and involves a higher radiation exposure. These considerations have largely limited QCT to research settings. More recent work has indicated that ultrasound of the calcaneus may also be useful in bone mineral evaluation. Although ultrasound cannot measure BMD directly, it can provide information that relates not only to the quantity of bone mineral but also to the interconnectivity of the trabecular pattern, which may be indicative of structural integrity.

SPA was the first of the quantitative techniques to be developed, and clinical bone mineral measurements were performed with it in the Division of Nuclear Medicine at Children’s Memorial Hospital from 1981 to 1993. SPA, which uses a photon beam from a sealed radionuclide source, was employed primarily for measuring cortical bone in the radius. The clinical advantages of SPA include the availability of normal values for children and extensive experience in its use for following children with bone mineral disorders. SPA’s major disadvantage is its inability to measure the axial skeleton, particularly trabecular bone in the spine.

More recently, DXA has been developed, and its versatility has greatly expanded the scope of bone mineral measurements in clinical practice. By analyzing the absorption of x-ray beams of two different energies, DXA measures multiple anatomic sites including the lumbar spine, hip, radius and whole body. Currently, well-established pediatric normal values are available only for the lumbar spine. Because evaluation of cortical bone is also important, we correlated DXA and SPA measurements of the radius and defined a regression that calculates "SPA-equivalent values" from the DXA measurements. This permits us to use established pediatric SPA normal values for DXA measurements of the radius.

DXA is the current preferred method of bone mineral analysis; it has been available at Children’s Memorial Hospital since 1993. Our standard bone mineral examination includes the measurement of trabecular bone in the lumbar spine and the measurement of cortical bone in the radial diaphysis by DXA. Where clinically indicated, the hip is also examined, and whole-body bone mineral analysis will be added shortly. DXA results are reported as BMD values, along with the number of standard deviations from the mean of age- and sex-matched controls (Z-scores) and the percentage of peak bone mass that has been achieved. These studies involve very small radiation exposures; an estimated effective dose equivalent for DXA measurement of the lumbar spine is 1mSv (0.1rem). Furthermore, the accuracy and precision (1%) of these studies have made them very useful for following bone mineralization longitudinally.

Which children have disorders of bone mass accumulation?

A careful family history for disorders of bone mass accumulation should be performed for otherwise normal children and includes reporting of an unusual fracture frequency, early-onset osteoporosis or a disabling complication of osteoporosis. The clinician should remember that normal statural growth does not necessarily imply normal bone mass accumulation.

Most children with chronic diseases are candidates for the inadequate accumulation of bone mass during childhood, either from the disease process itself, its therapy, or from associated problems such as inadequate nutrition or immobility. The astute clinician will be cognizant of the possibility of a disorder in bone mass accumulation and consult with a specialist in medical bone disease for the proper evaluation. Although not an exhaustive list, Table 2 lists those children at particular risk for inadequate bone mass accumulation.

Be aware of possible bone mass problems

Many new and effective therapeutic choices exist for the child with metabolic bone disease and inadequate accumulation of bone mass. It is most important, however, for the pediatrician to be cognizant of the possibility that her/his patient has such a disturbance.

Bone mass measurement and sophisticated metabolic evaluation are now commonly available at high-caliber pediatric institutions such as Children’s Memorial Hospital in Chicago. Since abnormalities of bone mass accumulation may not be repaired outside of the childhood years, an increased understanding of the possibility of these diverse group of disorders will allow the most effective therapies to be instituted at the most appropriate times in the child’s life.

FOR FURTHER READING (annotated list)

1. Broadus A: Mineral Balance and Homeostasis, A Primer on the Metabolic Diseases and Disorders of Mineral Metabolism, (3rd ed), Philadelphia:Lippincott-Raven, 1996, 57–63. A lucid discussion of the components of mineral balance, from ions to hormones to growth factors. The entire tome is worthwhile for the basics of bone cell biology as well as a thorough synopsis of clinical bone disorders in children and adults.

2. Kellie SE: Diagnostic and therapeutic technology assessment: Measurement of bone density with dual-energy X-ray absorptiometry. JAMA 1992;267:286–294. Reviews accuracy and precision of DXA and other techniques for measuring bone mineral as well as the efficacy of these techniques in the clinical evaluation of osteoporosis.

3. Shore RM, Langman CB, Donovan JM, Conway JJ, Poznanski AK: Bone mineral disorders in children: Evaluation with dual X-ray absorptiometry. Radiology 1995;196:535–540. Our data that correlates DXA and SPA measurement of the radius. The high correlation has permitted us to calculate SPA-equivalent values and thus use SPA normal standards with DXA measurements for clinical evaluations.

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