Bone Softening Diseases and Disorders of Bone Metabolism
Metabolic diseases of the bone are a heterogeneous group of skeletal disorders in which there is an error in formation, remodeling, or absorption of bone. Nearly 400 different conditions fall under the broad heading of constitutional disorders of bone, resulting in complex nosocology and classification.1 Further complicating matters, modern genomics has blurred the distinction between categories of dysplasia, dysostoses, and metabolic disorders by identifying a limited number of genetic defects associated with this group of bone malformation syndromes. Although the term metabolic disease implies a diffuse process, individual bones may be more severely affected than others, and only a few bones with metabolic defects may become symptomatic. It is unusual for a metabolic disease of bone to manifest at the craniovertebral junction (CVJ); when it does occur, the disease typically results in basilar impression and platybasia due to a loss of structural integrity at the skull base. Softening of the bony skull base may produce profound effects on neural structures that it normally supports and protects.
Some bone softening processes of the skull base are primary disorders of metabolism, such as osteogenesis imperfecta, a familial disorder of bone development. Others are secondary and result from a variety of causes, including nutritional abnormalities and hormonal disorders. Although Paget disease is not a metabolic disease, it can involve the skeleton diffusely and occasionally affects the CVJ. All of these diseases have the common feature of skull base deformity arising from the weakened mechanical properties of the skull base.
Certain heritable disorders such as Down syndrome, with inborn errors of metabolism, may not produce bone softening but manifest in the CVJ region. As a result of metabolic errors, osseous development is impaired and, in some cases, results in abnormal craniovertebral architecture. Hereditary connective tissue disorders may be associated with ligamentous laxity in the CVJ region, which can progress to instability. Rather than the basilar impression seen in bone softening metabolic diseases, patients with these inherited disorders present with stenosis at the CVJ from associated kyphotic deformity.
The terms basilar invagination, basilar impression, and platybasia were used interchangeably by Chamberlain in his original description, leading to some confusion.2 This chapter follows the convention established by VanGilder, which defines basilar invagination as a congenital or primary prolapse of the vertebral column into the skull base.3 Basilar impression refers to a progressive infolding of the skull base or secondary basilar invagination. Platybasia, which frequently accompanies both basilar invagination and basilar impression, refers to a flattening of the anterior skull base. In platybasia, the basal angle formed by the plane of the frontal fossa and the plane of the clivus is an abnormally obtuse angle. A characteristic appearance is seen in basilar impression and platybasia associated with bone softening disease affecting the skull base. The bones surrounding the foramen magnum are folded upward and inward around the upper cervical spine, as a ball of putty would deform over the end of a stick. In most cases, the bones are normal in size but distorted in shape. However, in some cases, the molded bones are eroded or even enlarged as a result of the pathological metabolism.
Bone Remodeling
Bone is a specialized form of connective tissue, composed of compact bone and cancellous bone. The histological characteristics are the same for both types, but compact bone lacks the numerous interconnecting cavities of cancellous bone. Cortical bone forms 80% of the volume of the skeleton and is found primarily in long bones. Cancellous bone, constituting 20% of the volume but 70% of the surface area, is found primarily in the vertebrae, the flat bones, and the ends of long bones.4,5 Bone remodeling occurs only on the surface of bone; therefore, rates of remodeling are greater in cancellous bone because of a higher surface-to-volume ratio. Abnormalities in bone remodeling will differentially affect the weight-bearing bones of the axial skeleton, which have a larger proportion of cancellous bone. Accordingly, the pathological effects of metabolic bone disease are generally manifested in the spine, pelvis, and ends of larger long bones, only rarely affecting the CVJ.
Bone is composed of three types of cells (osteoblasts, osteocytes, and osteoclasts) and a mineralized organic matrix. Osteoblasts cover the surface of bone like an epithelial lining and are responsible for bone apposition. They synthesize the organic components of the bone matrix and deposit the inorganic components. Once the osteoblast is completely surrounded with bone matrix, it becomes an osteocyte. Osteocytes are responsible for maintaining the bone matrix, providing nutrient transportation through the interconnected lacunes and canaliculi in which they lie. Osteoclasts break down bone matrix by secreting enzymes that liberate calcified ground substance and break down the organic matrix. Osteoclasts are found on the surface of bone in excavated depressions called Howship lacunae.
Type I collagen, a fibrous protein, comprises the majority of the organic matrix of bone, accounting for ~90% of bone by weight. The remainder of the organic material, proteoglycans and glycoproteins, forms an amorphous ground substance in bone. Calcium and phosphorus are the two major inorganic components of bone matrix. They exist in the form of hydroxyapatite crystals or amorphous calcium phosphate. Hydroxyapatite crystals lie along the collagen fibrils and are surrounded by amorphous ground substance. This association of hydroxyapatite to the collagen fibers gives bone its characteristic hardness and strength.
Bone formation is a product of bone remodeling, a recapitulating process of osteoclastic stimulation, bone resorption, osteoblastic migration, matrix synthesis, and mineralization. Primary bone, the first bone tissue to appear, contains randomly arranged collagen fibers. This primary bone matures into secondary bone with organized lamellae through a process of bone resorption and subsequent rebuilding. Bone growth is rapid early in life because secondary bone is continually remodeled, with more bone laid down than resorbed. A net increase in bone formation continues until the third decade. Although net bone growth plateaus, remodeling continues throughout life as a perpetual cycle of bone resorption and formation.
In the majority of metabolic diseases of the skeleton, there is a net decrease in bone mass due to an imbalance between bone breakdown and bone remodeling.6 Osteoporosis is a condition in which there is reduced bone mass per unit volume in bone with otherwise normal chemical makeup. Osteoporosis refers to a diverse group of diseases in which the bone is porous or thin but the ratio of mineral to matrix is normal. Osteomalacia is a condition in which the organic bone matrix is abnormally mineralized. Rickets and osteomalacia represent the same pathological process; however, rickets refers to this process in children whereas osteomalacia is generally used to describe defective bone mineralization in adults after the closure of epiphyseal growth plates. The term osteopenia is used when the reduction of bone density in osteoporosis or osteomalacia becomes radiographically evident. Osteopenia may be completely asymptomatic but becomes clinically significant when the bone can no longer provide skeletal support and fractures.
Calcium Metabolism and Related Hormones
Calcium and phosphate homeostasis is regulated by bodily need. For instance, growing children are rapidly forming new bone and require additional calcium and phosphate. New calcium is derived through diet and is absorbed through the intestine with the aid of active vitamin D metabolites. Phosphorous is also absorbed through the intestine and is at least partly linked to calcium absorption. Renal filtration is responsible for excretion of plasma calcium. The total amount of calcium excreted by the kidney depends on the rate of reabsorption in the renal tubules. Resorption is increased and excretion decreased by parathyroid hormone (PTH). Phosphate excretion by the kidney is regulated in the opposite way by PTH (i.e., increasing excretion of phosphate). Vitamin D enhances renal tubular resorption of phosphate.
Vitamin D is converted to its active metabolite (1,25-dihydroxycholecalciferol) through a succession of reactions in the skin, liver, and kidney. Physiological levels of vitamin D combined with PTH promote bone resorption by stimulating osteoclastic activity. PTH is secreted by the parathyroid gland in response to decreased plasma calcium levels. In turn, increased PTH increases plasma levels of calcium by releasing it from bone. Calcitonin, secreted by the thyroid gland in response to increases in plasma calcium levels, promotes the movement of calcium and phosphate into bone. Estrogen has an inhibitory effect on bone resorption. As estrogen levels decline following menopause, bone resorption increases.
Calcium and phosphate metabolism as it relates to bone is a twofold process in which one part is involved in the maintenance of plasma calcium equilibrium and the other part is involved in the remodeling of bone. Both parts are intimately related, but the differentiation helps to explain the complex metabolic process and its relationship to metabolic bone disease. Vitamin D and PTH affect plasma levels of calcium and phosphate by altering intestinal absorption and urinary excretion. Calcitonin and PTH alter plasma levels of calcium by affecting the rate of bone resorption. Pathological alterations in calcium homeostasis may result in metabolic bone disease.
Metabolic Disorders
Osteomalacia refers to a diverse group of diseases in which mineralization of newly formed osteoid matrix is deficient. The most common cause of osteomalacia is vitamin D deficiency, but it is also associated with malabsorption syndromes. When osteomalacia occurs in association with chronic renal failure, it is considered to be a form of renal osteodystrophy. The pathogenesis of osteomalacia is complex, but the fundamental problem is one of osteoblast function. A deficiency of phosphate, vitamin D, and/or vitamin D metabolites is responsible for the defective osteoblast function. An abnormality of synthesis, maturation, and mineralization of matrix results in an overall reduced rate of bone formation. The greatest defect, however, is in mineralization, with a net effect of decreased bone mass and markedly diminished mechanical properties.
Skeletal deformities in rickets are more generalized and severe than in adult osteomalacia because the mineralization defect occurs in developing bone. Dwarfism, “pigeon” breast, and bowed legs are general features of rickets that typically do not occur in adult osteomalacia. The spinal manifestations of rickets are not as prominent as those of the long weight-bearing bones because there is less longitudinal growth in vertebrae. The cranial manifestations include craniotabes (thinning and softening of the skull bones) and dolichocephaly (a disproportionately long head).
Basilar impression secondary to osteomalacia has been reported to occur with rickets, nutritional deficiency, renal osteodystrophy, and hyperparathyroidism. Basilar impression occurs more frequently in rickets than in adult onset osteomalacia and is thought to develop during the first 2 years of life, when the rachitic skull base is unable to support the disproportionately large weight of an infant′s head.7,8 In some instances, primary basilar invagination is the result of skull base rickets that has “healed” and, therefore, is secondary rather than congenital. Once the deficiency has been corrected, the bone mineralizes normally and resists further deformation.
Many cases of basilar impression due to osteomalacia are neurologically asymptomatic and are discovered incidentally, particularly if the osteomalacia has “healed.” However, if the deficiency persists, basilar impression may be progressive with the gradual onset of neurological symptoms. Neurological deficits stemming from the foramen magnum region are protean, but long tract signs are the predominate finding in basilar impression. Some of these cases may also have a clinical presentation typical of a Chiari I malformation and have ectopic cerebellar tonsils with basilar impression. As a note of caution, nutritional deficiencies can lead to metabolic myopathy in addition to osteomalacia. Therefore, proximal weakness in a patient with osteomalacia may be a manifestation of associated myopathy rather than basilar impression and neural compromise.9
Related posts:
Primary Osseous and Metastatic Neoplasms of the Craniovertebral Junction
Congenital Malformations of the Craniovertebral Junction
Management of Vertebral Artery Dissections and Vascular Insufficiency
Traumatic Injuries of the Craniovertebral Junction
Management of Intramedullary Lesions of the Cervicomedullary Junction and High Cervical Spinal Cord
Aneurysms of the Craniovertebral Junction
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