Bone Metabolism and Osteoporosis and Its Effects on Spinal Disease and Surgical Treatments

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CHAPTER 271 Bone Metabolism and Osteoporosis and Its Effects on Spinal Disease and Surgical Treatments

Bone physiology as it relates to mineralization and resorption is of particular interest to neurosurgeons treating spinal disorders. Alterations in bone metabolism because of disease or normal aging can lead to fractures, spinal instability, and deformity, which in turn can cause chronic pain or neurological deficit. Poor bone quality secondary to unbalanced bone resorption may also have a significant impact on surgical planning inasmuch as impaired bone strength can result in implant failure in instrumented spinal procedures. Accordingly, a better understanding of bone physiology, regulating factors, and diseases of bone metabolism facilitates better decision making regarding patient management and surgical intervention and thus reduces the risk for postoperative complications.

The spinal column performs the primary functions of maintaining mineral balance, protecting the neural elements, and serving as points of attachment for muscles that act on the skeleton for movement and support. Structurally, bone consists of cortical and cancellous bone. Cortical bone is dense, rigid tissue that biomechanically is responsible for resisting torsional and shear loads. Cancellous bone, which is more prevalent in the spinal column, is composed of multiple interconnected horizontal struts. Biomechanically, cancellous bone provides resistance to compressive and shear stress.

Histologically, bone is composed of several basic cell types: osteoprogenitor cells (preosteoblasts and preosteoclasts, which originate from hematopoietic stem cells), osteoblasts, osteoclasts, and osteocytes, all of which work together to regulate and maintain the local tissues. Bone matrix, the major substance that surrounds bone cells, is composed of organic and inorganic components. The organic component consists largely of type I collagen, which provides stiffness and strength to bone. The remainder of the organic constituents include noncollagenous proteins such as proteoglycans, bone morphogenetic proteins (BMPs), osteonectin, osteocalcin, and bone sialoprotein. These proteins are vital in performing various functions such as regulating mineral content, bone resorption, and induction of osteoprogenitor cells. The inorganic component of bone matrix is the store of calcium and phosphorus as bone mineral. Calcium phosphate is maintained as crystalline hydroxyapatite and accounts for 99% of the body’s calcium. Calcium is packaged in mitochondrial granules and matrix vesicles, which are subsequently released during mineralization. Calcium within bone primarily provides structural integrity and is released into the circulation for regulating metabolic processes.

Bone Metabolism

Bone metabolism is the complex interconnected processes of bone formation and resorption. With balanced remodeling, older bone is continually being replaced by new bone with equal turnover. This process results in the release of minerals into the circulation, prevents accumulation of fatigued bone, and maintains a constant bony architecture. Remodeling begins when osteoclast stem cells become activated to mature osteoclasts and arrange themselves by forming tight attachment to bone. Osteoclasts then release hydrogen ions, which lowers the local pH and induces dissolution of hydroxyapatite. In so doing, osteoclasts bur through bone and create a resorption cavity. The restorative process is initiated by the maturation of preosteoblasts to osteoblasts and their subsequent mobilization to the newly formed defect. In the resorbed cavity, osteoblasts synthesize and secrete collagen-rich matrix, which then provides a surface for mineralization. The ability of the bony spine to provide structural support and protection of the neural elements is dependent on balanced remodeling. Bone turnover is balanced when the amount of resorbed bone is replaced by an equivalent quantity of newly formed bone. Excessive resorption with insufficient formation eventually results in osteopenia and impaired bone quality. Poor bone strength can lead to structural failure resulting in fractures, instability, and deformity.

Regulation of bone metabolism is multifactorial. Parathyroid hormone (PTH) is a polypeptide secreted by parathyroid chief cells. Secretion of PTH is stimulated by decreased circulating ionized calcium, which induces multiple organs to increase their calcium concentration. In the kidneys, PTH causes increased calcium reabsorption in the distal tubule of the kidney. PTH also inhibits reabsorption of phosphate from the proximal tubule, thereby preventing the reabsorbed calcium from being deposited as hydroxyapatite. PTH stimulates the production of 1α-hydroxylase, which leads to activation of vitamin D, which in turn increases calcium reabsorption in the gastrointestinal system. In bone, PTH demonstrates dose-dependent activity. At high doses, PTH binds to receptors on osteoblasts, and via the RANKL (receptor activator of nuclear factor κB ligand)-RANK system, osteoclasts are activated, which increases bone resorption. At low intermittent doses, PTH stimulates osteoblasts to form new bone without inducing osteoclastic activity.

Vitamin D is a steroid that also increases circulating calcium. Vitamin D is either produced in an inactive form from the skin or acquired nutritionally. The inactive form, vitamin D3, is formed from the skin by activation of 7-dehydrocholesterol by ultraviolet light. Vitamin D then undergoes 25-hydroxylation to form 25(OH)2D3 in the liver. The active form of vitamin D is then produced in the kidney with stimulation by PTH. Vitamin D functions by entering the cell nucleus to increase expression of proteins involved in calcium transport from intracellular stores within bone into the circulation.

Calcitonin is secreted by the parafollicular cells of the thyroid gland to prevent bone resorption. Calcitonin binds directly to receptors on osteoclasts, which decreases adherence of osteoclasts to bone and thus inhibits their activity. The resulting effect is stabilization of calcium storage in bone matrix. Calcitonin also blocks reuptake of calcium from the kidney to decrease the circulating calcium concentration.

Gonadal hormones also perform a regulatory function on bone metabolism by increasing bone formation and decreasing resorption. Estradiol stimulates osteoblast proliferation and subsequently the synthesis of bone matrix. Estrogen decrease overall bone resorption by inhibiting osteoclast activity. Androgens indirectly increase bone formation by providing a substance for aromatization to estrogen.

Glucocorticoids affect bone mass by inhibiting bone formation and promoting bone resorption. They disrupt normal bone synthesis by entering the cell nucleus and altering the normal bone-forming mechanisms for synthesis of collagen. Glucocorticoids also block calcium uptake by inhibiting the effect of vitamin D on absorption of calcium in the intestine.


Osteoporosis is a disease of unbalanced bone metabolism that results in low bone density with subsequently increased bone fragility and propensity for fractures. The World Health Organization (WHO) has defined osteoporosis as bone density that is 2.5 standard deviations (SD) below normal healthy bone. Loss of bone density to between 1 and 2.5 SD below normal has been defined as osteopenia. Osteoporosis is estimated to currently affect 10 million Americans, and an additional 18 million with significantly low bone density are deemed to be at high risk for the development of osteoporosis in their lifetime.1 By the year 2020, it is predicted that 14 million adults older than 50 years will have osteoporosis.2 Osteoporosis is most prevalent in North America and Europe; however, as overall life expectancy increases worldwide, the incidence of osteoporosis will similarly increase. Even though osteoporosis may be considered a normal process of aging, it is by far the most prevalent metabolic bone disease.

The primary concern for patients with osteoporosis is the increased risk for fractures. Osteoporosis-associated fractures most commonly involve the hip, spine, or wrist. More than 1.5 million osteoporotic fractures occur in the United States yearly.3 It is estimated that the annual incidence of hip fractures in the United States will exceed 6.3 million cases by the year 2050.4 Osteoporosis-related fractures can result in significant disability. Only a third of patients regain their premorbid level of function after a hip fracture, and a third require placement in a nursing home within 1 year of the fracture.57 Twenty percent of patients are no longer living 1 year after a hip fracture.5,8 Besides functional disability and chronic pain, osteoporotic fractures can result in significant anxiety, depression, emotional distress, decreased quality of life, and impaired social well-being.

The increased risk for vertebral compression fractures (VCFs) in patients with osteoporosis is of particular concern to spine care providers. Approximately half of all osteoporotic fractures are spine related.9 VCFs are responsible for 150,000 hospital admissions, 161,000 doctors visits, and more than 5 million days of restricted activity annually.10 It is estimated that 25% of women older than 50 years will suffer a symptomatic VCF during their lifetime.9 Although many VCFs are essentially asymptomatic or cause limited symptoms, they can also carry significant morbidity, with chronic pain related to the injury developing in up to a third of patients.11 In addition, VCFs can lead to progressive sagittal-plane deformity with concomitant reduced lung capacity. Kyphosis caused by severe or multilevel fractures can also alter the biomechanical stress at other segments and lead to increased risk for additional fractures.1214 This disease is associated with 23% higher mortality in women older than 65 years than in age-matched controls, with additional fractures contributing to increasing mortality.15

Osteoporosis also places a significant burden on national health care expenditures. The estimated health care cost for osteoporosis-associated fractures was $13.8 billion in 1995 and increased to $17 billion in 2001.2,16 This figure includes hospital and nursing home expenses, but the majority of the cost is for inpatient medical care. The projected national health care expenditure for osteoporosis is predicted to rise to $50 billion by the year 2040.2


Pathophysiology of Osteoporosis

The National Institutes of Health Consensus Conference defined osteoporosis as a skeletal disorder characterized by compromised bone strength, as reflected in the integration of bone density and bone quality, that predisposes to an increased risk for fracture.1 Bone density is determined primarily by two factors: one’s peak bone mass and the degree of bone loss throughout one’s lifetime. Bone quality is multifactorial and is dependent on one’s bony architecture, mineralization, ratio of bone formation to resorption, and accumulation of damage. Fractures are defined as mechanical failure as a result of a force or load applied to bone. Pathophysiologically, osteoporosis is a disease of decreased bone mass in the absence of a mineralization defect. Therefore, overall bone mass decreases while the remaining bone maintains normal calcification. Bone loss occurs when the rate of bone resorption is greater than that of new bone formation. With aging, osteoclastic resorption exceeds osteoblastic activity. The net effect is progressive loss of skeletal bone mass, which generally begins by the fourth decade.

Osteoporosis that occurs as a result of aging is termed primary osteoporosis. Primary osteoporosis is characterized by a slow phase and an accelerated phase. In the slow phase, the rate of resorption begins to exceed the rate formation, with 0.3% to 0.5% of bone mass being lost per year. The slow phase occurs in both men and women in older age groups and is hypothesized to be due to impaired vitamin D metabolism by the kidneys. The accelerated phase occurs only in postmenopausal women and is probably related to the loss of estrogen, which results in increased bone resorption. In the accelerated phase, bone mass decreases at a rate of 2% to 3% per year and the decrease continues for up to 10 years. Bone loss generally affects cancellous bone earlier and to a greater extent than cortical bone.

Several factors are protective against primary osteoporosis. Higher peak bone mass attained early in life provides a greater reserve to counteract the eventual increase in bone resorption later in life. Peak bone mass demonstrates linear growth until shortly after adolescence, at which time it consolidates for about 5 to 15 years. A balanced diet with sufficient calories, calcium supplementation, and vitamin D also reduces the risk for the development of osteoporosis. Regular impact loading and resistance exercises contribute to greater peak bone mass. Gonadal hormones are also protective against osteoporosis. Estrogen appears to be particularly important in maintaining bone mass in women. Estrogen suppresses resorption of cancellous bone and maintains balanced turnover between osteoblastic and osteoclastic activity. Administration of estrogen to postmenopausal women decreases bone loss, whereas estrogen deficiency results in increased bone resorption. In adolescents, gonadal hormones contribute to the development of maximal peak bone mass.

Several factors increase the risk for the development of osteoporosis. Late menarche or premature menopause, which results in decreased overall lifetime exposure to estrogen, increases one’s likelihood of becoming osteoporotic. Inadequate dietary intake of calcium through either poor nutrition or eating disorders can also lead to increased bone loss. A sedentary lifestyle or the absence of regular exercise likewise increases the risk for osteoporosis. Tobacco and excessive alcohol use also contribute to bone loss.

Ethnicity appears to be related to risk for the development of osteoporosis. White women have the greatest risk for osteoporosis, and this segment of the population also has a greater risk for vertebral and nonvertebral fractures than African American, Native American, and Asian women.17,18 African American women have higher overall bone mineral density (BMD) than white women throughout their lifetime. This discrepancy is reflected in a lower lifetime risk for hip fracture in African American women than in white women (6% for African American women versus 14% for white women).1

Secondary osteoporosis is a pathologic loss of bone density that occurs in the presence of an underlying medical condition. Common endocrinologic causes include hypogonadal states and hyperthyroidism. Gastrointestinal causes include malabsorptive diseases such as celiac sprue and inflammatory bowel disease. Hematologic disease and bone marrow dysplasia can also result in secondary osteoporosis. Chronic nutritional deficiencies can likewise lead to progressive bone loss. Various medications are associated with secondary osteoporosis, of which corticosteroids are the most commonly encountered. Corticosteroids, often used for immune suppression and treatment of asthma and rheumatoid arthritis, suppress bone formation and inhibit calcium absorption.

Pathophysiology of Osteoporotic Vertebral Fractures

Osteoporotic VCFs occur as a result of structural failure of the spinal column under physiologic loading. The ability of the vertebral body to support compressive forces is dependent on the inherent microarchitecture and material properties of the bone. The vertebral body is predominantly cancellous bone with a surrounding thin shell of dense cortical bone. The majority of axially directed loads are therefore resisted by cancellous bone. The microarchitectural properties of cancellous bone that contribute to structural integrity include trabecular thickness, porosity, and interconnectivity. Material properties that affect bone strength are the degree of mineralization, collagen composition, and lifetime accumulation of damage.

Physiologic loading generates axial compressive forces from activities such as lifting, bending, reaching, or falling. As the vertebral body is loaded, force is transmitted from the intervertebral disk to the end plates and then through the predominantly cancellous bone. In osteoporotic conditions, the cancellous bone suffers the greatest loss in bone density. Compressive mechanical strength is related to density squared, and therefore osteoporosis results in an exponential reduction in resistance to stress. Most commonly, fractures are a result of repetitive loading leading to material fatigue. As osteoporotic vertebrae are compressed, cracks form and grow. Ultimately, the vertebral body fails at a lower load than what would be required to induce failure with a single application of force.

Clinical Findings and Diagnosis

Osteoporosis is a progressive disease that generally becomes clinically relevant only when an individual suffers an osteoporosis-related fracture. Normal activity such as lifting, bending, reaching, or falling with low impact may exceed the loading capacity of osteoporotic bone and lead to failure. Mechanical failure results in an acute fracture, which in the spine is usually manifested as back pain, although subclinical VCFs may also occur. Generally, the pain associated with VCFs dissipates once the fracture heals, but in up to a third of patients the pain becomes chronic. VCFs are rarely associated with neurological compromise. However, multiple fractures can lead to progressive kyphosis. With global sagittal imbalance, patients may experience decreased functionality, impaired social well-being, and in severe cases, decreased pulmonary function.

The initial evaluation of a patient suspected of having osteoporosis includes BMD testing, which is repeated serially if pharmacologic treatment is initiated. Younger patients with severe osteopenia may warrant additional hematologic studies or a bone marrow biopsy.

Bone Mineral Density

The current standard for measurement of BMD is dual-energy x-ray absorptiometry (DEXA). DEXA scans evaluate BMD at clinically relevant locations such as the hip and spine, which are particularly prone to osteoporosis-related fracture. DEXA is a favorable screening tool because it exposes the patient to a low dose of radiation (90% less than with a standard chest radiograph). Standard spine DEXA values are obtained by scanning the lumbar spine in the posteroanterior plane from L1 to L4, with a total value for the four sites combined also being reported. BMD is expressed as the bone mineral content (grams) divided by the area (centimeters squared). Spine BMD may be falsely elevated in older patients with excessive osteophytes and calcification of disks or surrounding vasculature. BMD may also appear abnormally low in patients who have previously undergone laminectomy. BMD assessment of the hip includes scanning of the femoral neck, greater trochanter, intertrochanteric region, and total femur.

A patient’s BMD is compared with a Z score (BMD for healthy gender- and age-matched controls) and a T score (BMD for normal healthy young controls at peak bone mass). The WHO defines a BMD of less than 1 SD below the T score as being within normal limits (osteopenia). Osteoporosis is defined as a BMD greater than 2.5 SD below the T score. Severe osteoporosis is a BMD that is greater than 2.5 SD below the T score with at least one osteoporosis-related fracture. Based on the WHO classification, it is estimated that 94% of women older than 75 years meet the criteria for osteopenia, with 38% of women in this age group having osteoporosis.19 BMD values also correlate with fracture risk. Each 1-SD decrease in age-adjusted BMD measurement equates to a 1.5-fold increase in fracture risk.

Additional methods for assessing BMD include plain film densitometry or simple measurement of the cortex of the metacarpal or other tubular bones on standard radiography. Single-photon absorptiometry measures differences in photon absorption between bone and soft tissue. For ultrasound assessment, two transducers are placed opposite each other at the calcaneus. BMD can be determined by measuring broadband attenuation of the ultrasound beam through the calcaneus. Ultrasonography has proved to be effective in predicting risk for certain osteoporosis-related fractures. Computed tomography (CT) is becoming a useful instrument for assessing BMD. CT scanning at the midpoint of the vertebra can measure the BMD of cancellous and cortical bone, as well as the entire vertebral body. Therefore, both three-dimensional volumetric analysis and selective assessment of cancellous bone are possible with CT imaging. Disadvantages of the use of CT include the necessity for special calibration of the equipment before scanning, as well as variability in results with minor alterations in the location of measurement.

Biochemical Markers

Biochemical markers for bone formation and bone resorption can be quantified as a means of determining the actual rate of bone metabolism. Enzymes and proteins synthesized by osteoblasts and osteoclasts or osteoclast-induced degradation products are measured in serum or urine to assess bone turnover. These markers for bone remodeling can be used to determine risk for the development of osteoporosis. Biochemical markers are also used to monitor disease progression and responsiveness to therapy.

Markers of bone formation are noncollagenous proteins produced by osteoblasts, which are elevated in serum with increased activity. Bone-specific alkaline phosphatase is a product of osteoblasts and osteoblast precursors and is quantified with the use of monoclonal antibodies. Osteocalcin is a 49-residue polypeptide that is associated with 1,25-dihydroxyvitamin D3 activity and reflects osteoblastic synthesis and deposition of new bone. Additional markers of bone formation include type I collagen propeptides. Type I collagen is the major product of osteoblasts, and immunoassays for type I collagen propeptides provide a nonselective index of total bone formation activity in the body.

Markers of bone resorption reflect increased osteoclastic activity. Such markers include products secreted by osteoclasts, as well as collagen breakdown products. Biochemical markers of collagen degradation are the C- and N-terminal telopeptides of type I collagen cross-links (CTx and NTx). CTx and NTx are measured in urine and are the most sensitive indices of collagen breakdown, with NTx being most commonly referenced. Pyridinoline and deoxypyridinoline are collagen cross-linking amino acids that are excreted in urine when collagen is degraded. Pyridinoline and deoxypyridinoline are quantified with high-performance liquid chromatography. Bone is the predominant reservoir of type I collagen in the body and is therefore the major source of pyridinoline in urine. Collagen cross-links such as deoxypyridinoline are not unique to bone, however, and thus urine concentrations of these markers may not accurately reflect bone turnover. Serum markers for the osteoclast-specific isoform of tartrate-resistant acid phosphatase reflect activity of this lysosomal enzyme in bone resorption. Hydroxyproline is another urinary marker of bone resorption, but its utility is limited by its lack of specificity for bone and variability attributable to differences in diet and degradative losses in the liver.

Biochemical markers are primarily useful for determining risk for the development of osteoporosis and for assessing responsiveness to therapy. Serum markers are generally less variable than urinary markers, which need to be corrected based on creatinine clearance. Studies have demonstrated that levels of bone-specific alkaline phosphatase, osteocalcin, and NTx are higher in postmenopausal women than in premenopausal women.20 With bisphosphonate alendronate therapy, however, alkaline phosphatase, osteocalcin, and CTx levels have been shown to decrease 40% to 50% over a period of 6 to 12 months.21 NTx was the most responsive marker for measuring therapeutic response. Additional studies have suggested that NTx and CTx correlate significantly with BMD and risk for fracture.20

Conservative and Medical Management

Preventive measures remain among the most important and effective strategies for managing osteoporosis. Adequate nutrition with an appropriate balance of calcium and vitamin D is essential for optimizing bone quality. Calcium supplementation in the form of calcium carbonate or calcium citrate is primarily effective for postmenopausal women. Vitamin D supplementation is also beneficial, with one study demonstrating that 1200 mg of calcium and 600 to 800 IU of vitamin D result in a 40% decrease in hip fractures and a 16% decrease in mortality.22 Regular weight-bearing, impact exercise increases peak bone mass and thereby reduces the risk for osteoporosis. Wolff’s law states that bone forms by appositional growth in areas of increased stress. With impact loading, differences in electronegative potential occur across compressed surfaces, which subsequently stimulates bone formation. Subjects randomized to aerobics and weight-training programs demonstrate a 5.2% increase in spine density over subjects treated only with calcium supplementation.23

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