The Impact of Rheumatic Diseases and Their Treatment on Bone Strength Development in Childhood

Genetic Determinants of Bone Mass

It is estimated that heredity determines from 50% to 85% of the skeletal mass. ^, Environmental variables, including those related to prenatal factors, endocrine and nutritional influences, mechanical forces, and other risk factors, account for the remainder. The genetic basis at the molecular level by which bone mass and strength are determined have yet to be fully elucidated. Many genes may be involved, and several polymorphisms have been reported, including those for interleukin (IL)-6, vitamin D receptors, calcitonin receptor, transforming growth factor-β, estrogen receptor-α, osteocalcin, apolipoprotein E, osteoprotegerin (OPG), androgen receptor, osteopontin, osteonectin, and type I collagen. ^{, ,} Genetic studies suggest that a combination of genotypes at several loci may have a major role in determining bone mineral density (BMD) and bone mineral content (BMC). In adults, genome-wide association studies (GWAS) have identified more than 50 loci associated with BMD. In children, GWAS have identified the impact of the CPED1-WNT16-FAM3C locus on total BMD. ^,

An association with loci on SP7/Osterix , RIN3 , RBFOX1 , and TBPL2 has also been reported. Furthermore, gender-dependent genetic influences on BMD have been suggested. During childhood and adolescence, the effects of the 9p21.3 locus on aBMD at radius and IZUMO3 on total BMD at multiple sites have been reported for boys. In contrast, the SPTB locus is related to BMD at multiple sites only in girls.

Bone Modeling, Remodeling, and Biochemical Markers of Bone Formation and Resorption

Bone remodeling is the process by which the skeleton refreshes itself by working on the same bone surfaces, engaging first in resorption to remove old, damaged bone and then formation to replace the old bone with new, healthy tissue. In contrast, modeling is the process by which the skeleton changes in size and shape, working on different bone surfaces. For example, as the tibia grows there is bone formation–driven periosteal apposition on the external cortical surfaces causing growth in width, and at the same time, resorption takes place on the endocortical surface, making the bone marrow cavity bigger. Both children and adults can undergo bone remodeling and thereby repair damaged bone, whereas bone modeling is largely unique to the pediatric skeleton and, as such, has important clinical implications. For example, because of bone modeling, children have a much greater capacity to increase bone density spontaneously or in response to bone-targeted therapy (such as bisphosphonates). Similarly, children have the unique potential to reshape vertebral bodies after spine fractures, a clinical phenomenon described later in this chapter.

Bone turnover in a growing skeleton facilitates bone formation and limits bone resorption in order for skeletal growth to occur. Studies of bone mineral metabolism generally assay a specific set of markers of bone formation and resorption in blood or urine. Table 48.1 summarizes the principal characteristics of commonly used biochemical markers of bone remodeling. However, there are many confounding factors in using these measures (e.g., urinary acidity, medications, magnesium concentration, diurnal variation, and renal function). Another limitation of using markers of bone formation and resorption is that these markers represent an average turnover from all skeletal sites of the body and consequently are not site specific. Moreover, additional difficulties are intrinsic in the interpretation of pediatric measurements, mainly because these markers reflect growth and remodeling. Therefore reference data for age, sex, and ethnicity are essential. Although these markers cannot be used for the diagnosis of osteoporosis, they are important in the study of bone turnover in pathological conditions, and they can be useful in the follow-up of patients during anti-osteoporotic treatment, for evaluation of compliance, and consideration in prognosis.

Measures of bone formation include the activity of bone-specific alkaline phosphatase, which is released during osteoblastic activity. Osteocalcin is a vitamin K-dependent, γ-carboxylated protein derived from osteoblasts. Its serum concentration reflects the portion of newly synthesized protein that does not bind to the mineral phase of bone and is released into the circulation. Serum carboxylterminal propeptide of type I procollagen (PICP) is also a marker of bone formation. PICP is a globular protein cleaved by a specific peptidase at the C-terminal end of the procollagen triple helix. Its concentration in blood directly reflects the number of collagen fibrils formed.

Plasma tartrate-resistant acid phosphatase is a marker of bone resorption. This labile enzyme is released during osteoclastic activity. The urinary concentration of the deoxypyridinoline cross-linked telopeptide of type I collagen represents hydroxylysyl and lysyl post-translational components of the cross linkage of type I collagen that stabilize the molecule. It is measured in the urine in relation to the concentration of creatinine. These crosslinks are reflective of mature collagen breakdown and are also a marker of bone resorption. Deoxypyridinoline is found in large amounts only in type I collagen; therefore its urinary excretion reflects the metabolic breakdown of that molecule. Urinary hydroxyproline has been used similarly. Telopeptides of type I collagen (C terminal: CTX-I; N terminal: NTX-I) are fragments of collagen released into the circulation when bone is resorbed. These peptides are nonhelical fragments of type I collagen that contain the crosslinking regions. The N -terminal cross-linked telopeptide of type I collagen, NTX-I, is measured in urine, whereas assays for its C-terminal counterpart, CTX-I, are measured in blood samples after an overnight fast.

Calcium-Regulating Hormones

Among extrinsic factors, an adequate intake of calcium and vitamin D is a relatively important factor in achievement of peak bone mass.

Thus assessment of bone mineral metabolism includes assays for calcium-regulating hormones such as parathyroid hormone (PTH), 25-hydroxyvitamin D ₃ [25-(OH)D ₃ ], and 1,25-dihydroxyvitamin D ₃ [1,25-(OH) ₂ D ₃ ]. The primary function of PTH is to maintain the ionized calcium concentration of the blood within a narrow physiological range. Hypocalcemia stimulates PTH secretion, whereas hypercalcemia suppresses its secretion. PTH regulates calcium homeostasis by acting on the major calcium reservoir of the body, the skeleton. It stimulates osteoclastic activity and thereby bone resorption. It also stimulates the conversion of 25-(OH)D ₃ to 1,25-(OH) ₂ D ₃ .

The principal source of 25-(OH)D ₃ is dietary vitamin D ₂ . Ultraviolet light also endogenously stimulates the production of vitamin D ₃ from 7-dehydrocholesterol in the skin. 25-(OH)D ₃ is biologically inactive and is hydroxylated in the kidneys to the 1,25-(OH) ₂ D ₃ hormone. This hormone, calcitriol, stimulates intestinal absorption of calcium, thereby elevating the serum calcium concentration. Receptors for 1,25-(OH) ₂ D ₃ are present on intestinal cells. Care must be taken in interpreting the results of measurement of the vitamin D hormones because the following factors influence the results: diet, malnutrition, the presence of diseases leading to malabsorption or a catabolic state, geographical location, and season of the year (sun exposure).

The Receptor Activator of Nuclear Factor-κB (RANK), RANK Ligand (RANKL), OPG System

Discovery of the receptor activator of nuclear factor-κB (RANK) signaling pathway in the osteoclast provided insight into the mechanisms of osteoclastogenesis and activation of bone resorption. OPG, RANK, and the RANK ligand (RANKL) are parts of a family of biologically related tumor necrosis factor receptor (TNFR)/tumor necrosis factor (TNF)-like proteins that regulate osteoclast function. RANK, a transmembrane signaling receptor, is mainly expressed by monocytes and macrophages; it is essential for osteoclast differentiation and activation and therefore for bone resorption. Its activation depends on binding with RANKL. OPG is a soluble protein that acts as a decoy receptor of RANKL, inhibiting osteoclast differentiation and activation, and thereby reducing bone resorption. To maintain bone homeostasis, balance in the RANKL, RANK, OPG system is required. The mature osteoclast, in response to activation of RANK by RANKL, undergoes internal structural changes that enable it to resorb bone.

The Mechanostat Model of Bone Strength Development in Childhood

According to the mechanostat theory, the development of bone strength in childhood is driven by mechanical loads. These loads induce bone tissue strain, which is monitored by the osteocyte system. When bone tissue strain exceeds a given threshold, osteocytes initiate an effector cascade that induces osteoblasts and osteoclasts to reinforce bone at the site of strain, ^, thus effectively adapting to mechanical stimuli. The key mechanical loads in childhood that stimulate bone strength development are increases in muscle forces and increases in bone length, both of which are maximal around the time of puberty.

The fact that muscle strength is essential for bone development is clear from animal and human ^, studies, and is underscored by the fact that children with congenital neuromuscular disorders consistently manifest low bone mass and bone fragility. The skeletal effects of weightlessness and anorexia, or the negative effect of low body mass index (BMI) on osteoporosis risk in postmenopausal women and the corresponding benefit of strength training predicted a relationship between weight, muscle activity, and bone health in children. Studies in children with rheumatic diseases and vertebral fractures, often with low BMD Z score (described in detail below), suggest a correlation between lean body mass, rather than total body mass, and bone health. More recent studies have confirmed this relationship and described its complexity. Bone adapts to changes in weight, but the hormonal axis, nutritional status, and requirements of mineral homeostasis prevent the mechanostat from protecting bone at weights far under or over healthy body weight. More recently, a cross-sectional study of nearly 900 Boston-area children using dual-energy X-ray absorptiometry (DXA) to assess BMD demonstrated that abdominal fat may negatively impact bone health. This may explain in part why lean mass correlates more strongly than total body mass with bone health. It is important to note that not all mechanical stress on bone produces the same effect on BMC. For example, swimmers have been shown to have a higher amount of lean mass and muscle cross-sectional area (mCSA) than controls with the same BMC. Nonetheless, the mechanostat will tend to maintain and promote bone homeostasis and normal bone mass.

Mechanisms of Bone Strength Loss in Pediatric Rheumatic Disorders