This article discusses the problem of osteoporosis in cerebral palsy. Osteoporosis remains a major health problem worldwide. Cerebral palsy is the most prevalent childhood condition associated with osteoporosis. Bone density is significantly decreased. Children with cerebral palsy often sustain painful fractures with minimal trauma that impair their function and quality of life. This article addresses the anatomy and structure of bone and bone metabolism, the clinical assessment of bone mass, the causes of osteoporosis and its evaluation and treatment in children with cerebral palsy.
Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Osteoporosis remains a major health problem worldwide, costing an estimated $13.8 billion in health care each year in the United States. Despite advances in treating osteoporosis in the elderly, no cure exists. Osteoporosis has its roots in childhood. Accrual of bone mass occurs throughout childhood and early adulthood, and peak bone mass is a key determinant of the lifetime risk of osteoporosis. Because the foundation for skeletal health is established so early in life, osteoporosis prevention begins by optimizing gains in bone mineral throughout childhood and adolescence.
Osteoporosis evaluation and prevention is relevant to children with cerebral palsy (CP). CP is the most prevalent childhood condition associated with osteoporosis. Bone density is significantly decreased, and children with CP often sustain painful fractures with minimal trauma that impair their function and quality of life. Preventing or improving osteoporosis and maximizing bone accrual during critical stages of growth will minimize the future lifelong risks of fractures in children with CP. This article addresses the anatomy and structure of bone and bone metabolism, the clinical assessment of bone mass, the causes of osteoporosis and its evaluation and treatment in children with CP.
Osteoporosis
Diagnosis in Adults
The diagnosis of osteoporosis in adults is well defined and based exclusively on the assessment of bone mineral density (BMD). Bone density is reported as a T-score which is the number of standard deviations more than or less than the mean for a healthy 30-year-old Caucasian (nonrace adjusted database) adult of the same sex. The World Health Organization classifies normal bone density as a T-score of −1 or higher. Osteopenia is classified as a T-score between −2.5 and −1, and osteoporosis is a T-score less than or equal to −2.5. If a person has a fracture and a T-score of less than −2.5, then they are considered to have severe osteoporosis. Fracture risk and treatment options have been well investigated and documented in adults. Every 1 standard deviation decrease in BMD is associated with a twofold increase in fracture risk. However, comparable information is limited in children.
Osteoporosis in Children
The risk of fracture associated with low BMD, the evaluation of osteoporosis, and treatment options in children are less well defined. However, over the past decade there have been advances in the diagnosis and diagnostic classifications for osteoporosis in children. The International Society of Clinical Densitometry released a position statement defining the parameters for the diagnosis of osteoporosis in children in 2008. Unlike adult osteoporosis, the consensus was that osteoporosis in children should not be determined based on densitometric criteria alone. The diagnosis of osteoporosis requires a clinically significant fracture history and low bone mineral content or bone mineral density (ISCD Pediatric Position Statement, 2008). The current definition for osteoporosis in children includes a BMD Z-score less than −2.0 adjusted for age, gender, and body size plus a clinically significant history of fracture: (1) 2 upper extremity fractures, or (2) vertebral compression fracture, or (3) a single lower extremity fracture. The Z-score is the number of standard deviations the patient’s BMD is more than or less than age-, sex-matched reference values.
Bone embryology, anatomy, and architecture
To begin to understand osteoporosis a basic understanding of bone embryology, anatomy, and architecture is needed. The musculoskeletal system is derived from embryonic mesoderm at the third week of gestation. Mesenchyme, a subtype of mesoderm, is responsible for bone, cartilage, muscle, tendon, and fibrous connective tissue formation. In the sixth week of gestation, the mesenchymal cells begin the process of ossification of long bones. By the seventh week the cells differentiate into cartilage-forming precursors of long bones. In the eighth week the mesenchymal cells differentiate into osteoblasts, osteoclasts, and chrondroclasts through the process of endochondral ossification. This process transforms cartilage into bone and continues throughout childhood.
Composition and Structure of Bone
The skeleton of the developing embryo is primarily composed of either fibrous membranes or hyaline cartilage, which provide the medium for ossification. The process of ossification of flat bones such as the skull, ileum, mandible, and scapula occurs through intramembranous ossification, whereas the long bones such as the tibia, femur, and humerus are formed through endochondral ossification. Each long bone is comprised of 2 wider ends (epiphyses), a tubular middle (diaphysis), and the developing zone between the 2 (metaphysis). A layer of cartilage (growth plate) separates the epiphysis and metaphysis in growing bones. This area becomes calcified and remodeled with bone when growth is complete. The outer layer of the bone is comprised of a thick dense layer of calcified tissue known as cortical bone, which provides strength to the bone. Eighty-ninety percent of the volume of cortical bone is calcified. Toward the metaphysis and epiphysis, the cortex becomes thinner and the space is filled with thin calcified trabeculae known as trabecular or cancellous bone. Only 15% to 25% of trabecular bone is calcified. The bone marrow, blood vessels, and connective tissue make up most of the space. There are also 2 surfaces that the bone has with the surrounding soft tissues. The external surface is the periosteal surface and the internal surface is known as the endosteal surface. These are lined with osteogenic cells, which maintain bone formation and absorption.
Bone Formation and Absorption
The rates of absorption and deposition are equal in nongrowing bones. This delicate balance keeps the total bone mass constant and serves an important role in maintaining the strength of bones. Bones will adjust their strength in proportion to the amount of stress placed on them. Bones thicken with heavy loads and change shape to provide the necessary support. Healthy load-bearing bones and their trabeculae have enough strength to carry a load without breaking suddenly or in fatigue. The deposition and absorption of bone aligns with stress patterns. New bone matrix replaces old brittle bone. This balance is maintained through the work of osteoblasts and osteoclasts.
Function of Osteoblasts and Osteoclasts
Osteoblasts are found on the outer surface of bone and in bone cavities. Osteoblast activity occurs in approximately 4% of all living bones. There is continual activity with new bone always being formed. At the same time that bone is being formed, bone is also continually being absorbed by osteoclasts. Osteoclasts are large multinucleated cells. They are active on less than 1% of bone surfaces at any one time. Absorption occurs when osteoclasts send out villus-like projections toward bone and secrete proteolytic enzymes, citric acid, and lactic acid, which dissolve the organic matrix of the bone and the bone salts. The fragments of bone salts and collagen are than digested by the osteoclasts. Osteoclasts tunnel out sections of bone. Once the osteoclasts complete the process, osteoblasts invade the tunneled out bone and begin to lay down new bone. Normal bones can detect and repair small amounts of microdamage. In some bones this damage can exceed the threshold, escape repair, accumulate, and result in fracture.
Frost describes a hypothesis of mechanical bone competence that depends on the interactions between a bone’s strength and the magnitude and types of peak voluntary mechanical load on a load-bearing bone during typical activities. Diseased bone or failure to achieve mechanical bone competence can result in nontraumatic fractures in childhood. This can be seen in children with CP.
Bone embryology, anatomy, and architecture
To begin to understand osteoporosis a basic understanding of bone embryology, anatomy, and architecture is needed. The musculoskeletal system is derived from embryonic mesoderm at the third week of gestation. Mesenchyme, a subtype of mesoderm, is responsible for bone, cartilage, muscle, tendon, and fibrous connective tissue formation. In the sixth week of gestation, the mesenchymal cells begin the process of ossification of long bones. By the seventh week the cells differentiate into cartilage-forming precursors of long bones. In the eighth week the mesenchymal cells differentiate into osteoblasts, osteoclasts, and chrondroclasts through the process of endochondral ossification. This process transforms cartilage into bone and continues throughout childhood.
Composition and Structure of Bone
The skeleton of the developing embryo is primarily composed of either fibrous membranes or hyaline cartilage, which provide the medium for ossification. The process of ossification of flat bones such as the skull, ileum, mandible, and scapula occurs through intramembranous ossification, whereas the long bones such as the tibia, femur, and humerus are formed through endochondral ossification. Each long bone is comprised of 2 wider ends (epiphyses), a tubular middle (diaphysis), and the developing zone between the 2 (metaphysis). A layer of cartilage (growth plate) separates the epiphysis and metaphysis in growing bones. This area becomes calcified and remodeled with bone when growth is complete. The outer layer of the bone is comprised of a thick dense layer of calcified tissue known as cortical bone, which provides strength to the bone. Eighty-ninety percent of the volume of cortical bone is calcified. Toward the metaphysis and epiphysis, the cortex becomes thinner and the space is filled with thin calcified trabeculae known as trabecular or cancellous bone. Only 15% to 25% of trabecular bone is calcified. The bone marrow, blood vessels, and connective tissue make up most of the space. There are also 2 surfaces that the bone has with the surrounding soft tissues. The external surface is the periosteal surface and the internal surface is known as the endosteal surface. These are lined with osteogenic cells, which maintain bone formation and absorption.
Bone Formation and Absorption
The rates of absorption and deposition are equal in nongrowing bones. This delicate balance keeps the total bone mass constant and serves an important role in maintaining the strength of bones. Bones will adjust their strength in proportion to the amount of stress placed on them. Bones thicken with heavy loads and change shape to provide the necessary support. Healthy load-bearing bones and their trabeculae have enough strength to carry a load without breaking suddenly or in fatigue. The deposition and absorption of bone aligns with stress patterns. New bone matrix replaces old brittle bone. This balance is maintained through the work of osteoblasts and osteoclasts.
Function of Osteoblasts and Osteoclasts
Osteoblasts are found on the outer surface of bone and in bone cavities. Osteoblast activity occurs in approximately 4% of all living bones. There is continual activity with new bone always being formed. At the same time that bone is being formed, bone is also continually being absorbed by osteoclasts. Osteoclasts are large multinucleated cells. They are active on less than 1% of bone surfaces at any one time. Absorption occurs when osteoclasts send out villus-like projections toward bone and secrete proteolytic enzymes, citric acid, and lactic acid, which dissolve the organic matrix of the bone and the bone salts. The fragments of bone salts and collagen are than digested by the osteoclasts. Osteoclasts tunnel out sections of bone. Once the osteoclasts complete the process, osteoblasts invade the tunneled out bone and begin to lay down new bone. Normal bones can detect and repair small amounts of microdamage. In some bones this damage can exceed the threshold, escape repair, accumulate, and result in fracture.
Frost describes a hypothesis of mechanical bone competence that depends on the interactions between a bone’s strength and the magnitude and types of peak voluntary mechanical load on a load-bearing bone during typical activities. Diseased bone or failure to achieve mechanical bone competence can result in nontraumatic fractures in childhood. This can be seen in children with CP.
Markers of bone metabolism
Osteogenic Growth Factors
Insulin-like growth factors (IGF) are polypeptides that are synthesized in multiple tissues including bone. These peptides enhance the function of mature osteoblasts, therefore increasing bone matrix synthesis. Insulin-like growth factors inhibit bone collagen degradation and increase collagen synthesis, which help to maintain the bone matrix and bone mass. Alkaline phosphatase is secreted by osteoblasts while actively depositing bone. This activates collagen fibers and causes the deposition of calcium salts. The blood level of alkaline phosphatase is a good indicator of bone formation.
The Role of Calcium and Vitamin D
Vitamin D plays a critical role in the mineralization of bone. It is produced in the skin through exposure to sunlight. Vitamin D is biologically inert and must undergo 2 hydroxylations, first in the liver and then the kidneys to become active ( Fig. 1 ). The biologically active form is 1,25-dihydroxyvitamin D [1,25(OH) 2 D]. Its role is to maintain serum calcium in the normal range. It does this by increasing the absorption of calcium in the intestines and signaling stem cells in the bone to become mature osteoclasts. These osteoclasts then mobilize calcium from bone into circulation. Vitamin D is found naturally in small amounts in some foods. Oily fish such as salmon, mackerel, and fish liver oils contain vitamin D. Bread products, cereals, milk, and other dairy products are fortified with vitamin D, although the percentage of fortification on the label may not accurately reflect what is found in the food.
Vitamin D plays a role in bone mineralization by maintaining adequate levels of calcium and phosphorus in the blood. This allows the osteoblasts to lay down bone matrix. The production of 1,25(OH) 2 D is regulated by serum calcium levels through the action of parathyroid hormone (PTH) and phosphorus. As vitamin D stores become depleted due to lack of sunlight exposure or dietary deficiency, intestinal absorption of calcium decreases from 30% to 40% to 10% to 15%. The decrease in calcium levels leads to an increased secretion of PTH. PTH signals the renal conversion of 25(OH)D to 1,25(OH) 2 D indirectly through renal wasting of phosphorus resulting in decreased intracellular and blood levels. Hypophosphatemia in turn results in the increase in circulating concentrations of 1,25(OH) 2 D. Multiple other hormones associated with growth and development (growth hormone [GH] and prolactin) also indirectly increase renal production of 1,25(OH) 2 D.
The 1,25(OH) 2 D induces pre-osteoclasts to mature into osteoclasts. The osteoclasts in turn release hydrochloric acid and proteolytic enzymes that dissolve bone and matrix and release calcium into the extracellular space. 1,25(OH) 2 D also increases the expression of alkaline phosphatase, osteocalcin, osteopontin, and cytokines in osteoblasts.
Factors impacting bone mass
Osteoporosis is a disease characterized by a reduction in bone mass accompanied by micro-architectural changes that reduce the bone’s mechanical loading capability and increase its susceptibility to fractures. Acquisition of BMD is multifactorial and includes nutritional factors, genetics, hormonal influences, and growth factors. Gains in bone size and bone mineral content during childhood and adolescence are achieved only when environmental factors are favorable. Anorexia nervosa, exercise-induced amenorrhea, cystic fibrosis, inflammatory bowel disease, celiac disease, and rheumatologic disorders are associated with early deficits in bone mineral.
Bone acquisition and remodeling is controlled by mechanical and metabolic factors. Normal skeletal growth, the progression of puberty, and bone mineral accrual all require appropriate hormonal influences, including thyroid hormone, GH, IGF, and sex steroids. Bone growth is largely dependent on GH before puberty. Later, sex steroids become essential for the completion of epiphyseal maturation and mineral accrual in adolescence. The importance of normal endocrine function for bone mineral accrual is highlighted by clinical deficiency states. Reduced bone mineral density is commonly seen in GH-deficient children, and has been noted in disorders of estrogen resistance and aromatase deficiency. Malnutrition, immobility, sex steroid deficiency, and other factors can interrupt bone mineral accrual and have been found to be a contributing factor to early bone loss in children with CP.
Overall, appropriate gains in bone size and mineral content are achieved only when environmental conditions are favorable. Frost has discussed the idea that gene expression patterns in utero create baseline bone conditions at birth, including basic bony anatomy and anatomic relationships and neurologic and muscular anatomy and physiology. One also has the “machinery” to increase the strength of a load-bearing bone as needed by adapting to conditions placed on the bone during typical activities. However, factors that decrease a load-bearing bone’s strength could potentiate nontraumatic fractures. According to the “mechanostat hypothesis,” this could be the result of inadequate modeling, excessive disuse mode remodeling, impaired detection or repair of microdamage, degraded properties of bone that potentiate microdamage or a combination of the these.
Adolescence is typically a period of maximal bone accrual. Recent studies suggest that attainment of peak bone mass occurs at a younger age than was previously believed, with the average age closer to 18 to 25 years than 30 years. Twenty-five percent of peak bone mass is acquired during the 2-year period surrounding peak height velocity and at least 90% is reached by age 18 years. If the process of bone accrual is disrupted during this sensitive period, profound and lifelong osteopenia can result. The label “female athlete triad” refers to a syndrome of disordered eating, amenorrhea, and osteopenia seen in adolescent women who engage in intensive physical training. Expanding clinical experience with this syndrome confirms that the consequences of early osteopenia can be devastating. Premature fractures can occur, and lost bone mineral density may never be regained. The characteristics of affected athletes may be analogous to those of pubertal children with CP, in whom impaired oral intake results in undernutrition and suboptimal body weight, delayed menses, and pubertal progression. This suggests a disruption of the hypothalamic–pituitary–gonadal (HPG) axis and abnormal hormone status.
Assessment of bone health
The assessment of bone density is important for 3 reasons: to diagnose osteoporosis, to predict future fracture risk, and to monitor therapy.
Assessment of Bone Density Using Dual Radiograph Absorptiometry
Dual radiograph absorptiometry (DXA) is the most widely used method for assessment of BMD and is considered the “gold standard”. DXA uses 2 different radiographic energies to record attenuation profiles at 2 different photon energies. Attenuation is largely determined by tissue density and thickness. At a low energy, bone attenuation is greater than soft tissue attenuation. At high energy, they are similar. This allows the distinction between bone and soft tissue. The energy absorption of the 2 different energy radiographic beams is used to provide estimates of the amounts of bone mineral. The radiographic photons are collimated into a fan beam that passes through the patients and the photons are selectively attenuated by the bone and soft tissue. After the beam passes through the patient, it is passed to a radiographic detector whereby the intensity of radiation is recorded. This provides a 2-dimensional measurement dependent on the size of the bone and does not separate cortical and trabecular BMD. It can measure central skeletal sites (hip and spine). Extensive epidemiologic data in adults have shown correlations with bone strength in vitro. The DXA scan has been validated in adults and is widely available in the United States ( Fig. 2 ).
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