Bone Function and Structure

Bone serves as a mechanical support for musculoskeletal structures, as protection for vital organs, and as a metabolic source of ions, especially calcium and phosphate. Despite its appearance, bone is an active tissue. To maintain its biomechanical competence, bone tissue undergoes continuous change and renewal so that older bone tissue is replaced by newly formed bone tissue. Approximately 20% of bone tissue is replaced annually by this cyclic process. There are two types of bone cells: osteoclasts, which resorb the calcified matrix, and osteoblasts, which synthesize new bone matrix.⁶⁵

Osteoclasts are localized on the endosteal bone surfaces. Their origin is hematopoietic, and they share a common precursor with the monocyte macrophage. Osteoclasts are large multinucleated cells with an average of 10 to 20 nuclei. They have a special cell membrane with folds that invaginate at the interface with bone surface, called the ruffled border. To induce resorption of bone and the mineralized bone matrix, osteoclasts produce proteolytic enzymes in this ruffled border.

Osteoblasts are derived from mesenchymal cells. The role of osteoblasts is mineralization of the matrix through budding of vesicles from their cytoplasmic membrane. These vesicles are rich in alkaline phosphatase. Osteoblasts secrete all the growth factors that are trapped in the matrix.

Bone Remodeling

Bone remodeling is a process that allows removal of old bone and replacement with new bone tissue. This process allows maintenance of the biomechanical integrity of the skeleton, and it supports the role of bone in the provision of an ionic bank for the body and mechanical support. Bone remodeling has five phases.

This process is cyclical, starting with bone resorption and finishing with bone formation. In adult human bone, each cycle of remodeling lasts 3 to 12 months. The signal that stops osteoclastic activity is not yet completely defined. After bone resorption, the reversal phase starts, which involves osteoblastic activity. Then the osteoblasts start to fill the resorption cavity. During the process of osteoclastic activity, the growth factors that are stored in the bone matrix are released and subsequently stimulate osteoblastic proliferation.

This process of bone resorption and formation is called coupling. The ideal situation in the coupling process is equilibrated bone formation and resorption. In osteoporosis, however, there is disequilibrium between resorption and formation. In osteoporosis the coupling favors resorption that results in bone loss.

The number of active remodeling units in trabecular bone is about 3 times greater than in cortical bone. The physical endurance of any bone is affected by the percentage of cortical bone involved in its structure. Trabecular bone is more active metabolically than cortical bone because of the considerable surface exposure areas. Consequently, more bone loss occurs at the trabecular areas when resorption is greater than formation. The vertebrae consist of 50% trabecular bone and 50% cortical bone, whereas the femoral neck consists of 30% trabecular bone and 70% cortical bone. When bone turnover increases, bone loss and osteoporosis occur in the vertebrae before they occur in the femoral neck.

Pathogenesis

Peak adult bone mass is achieved between ages 30 and 35 years. Bone mass at any point in life thereafter is the difference between the peak adult bone mass and the amount that has been lost since the peak was reached. Age-related bone loss is a universal phenomenon in humans. Any circumstances that limit bone formation or increase bone loss increase the likelihood that osteoporosis will develop later in life. Measures that can maximize peak adult bone mass are clearly desirable.

Trabecular (or cancellous) bone represents about 20% of skeletal bone mass and makes up 80% of the turnover media. The cortex makes up only 20% of the turnover media and is made of compact bone. It represents 80% of skeletal bone mass. In both cortical and trabecular bone, bone remodeling is initiated with the activation of osteoclasts. The resulting resorption sites are then refilled by osteoblastic activities, a process called bone formation. If the amount of bone resorbed equals the amount formed, the bone loss is zero. The remodeling process does not result in zero balance after age 30 to 35 years, however, and after this age the normal process of remodeling results in bone loss.⁶³

Certain conditions, such as hyperparathyroidism or thyrotoxicosis, can increase the rate of bone remodeling. These conditions increase the rate of bone loss, which results in high-turnover osteoporosis. The secondary causes of osteoporosis are associated with an increased rate of activation of the remodeling cycle. Although factors such as calcium intake, smoking, alcohol consumption, physical exercise, and menopause are important factors in determining BMD, genetic factors are the major determinant and contribute to 80% of the variance in peak BMD.¹⁶ Fracture incidence related to osteoporosis is lower in men than in women because the diameter of vertebral bodies and long bones is greater in men at maturity and bone loss is less (about half that of women) throughout life.⁶⁷

Classification of Osteoporosis

Osteoporosis can be primary or secondary to other disorders that result in bone loss. The most common causes of osteoporosis are listed in Box 41-1. The most common type of osteoporosis is either postmenopausal or age related.⁵⁶

Primary osteoporosis is the rare disorder of idiopathic juvenile osteoporosis. This type of osteoporosis typically occurs before puberty (between ages 8 and 14 years), and patients present with osteoporosis that is progressive over 2 to 4 years in association with multiple axial or axioappendicular fractures. Remission usually occurs by the end of the 2- to 4-year course.³⁶ In this type of osteoporosis, the process of bone formation is normal but osteoclastic activity increases, resulting in increased bone resorption. This type of osteoporosis is most evident in the thoracic and lumbar spine and needs to be distinguished from juvenile epiphysitis or Scheuermann disease. It is usually self-limiting, but the radiographic appearance might not return to normal. The laboratory values are typically normal, and the diagnosis is made by exclusion.

Hormones and Physiology of Bone

The rate of bone remodeling can be increased by parathyroid hormone (PTH), thyroxine, growth hormone, and vitamin D (1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃]). It can be decreased by calcitonin, estrogen, and glucocorticoids.⁴⁶

The major hormone for calcium homeostasis is PTH. It is secreted by the parathyroid glands, which are located behind the thyroid glands. The level of plasma calcium is the major moderator of the secretion of PTH, which regulates the plasma calcium ion (Ca²⁺) concentration in three ways:

PTH also reduces proximal tubular reabsorption of phosphate. In general, PTH increases serum calcium concentration and mostly tends to decrease serum phosphate concentration.

Calcitonin is a hormone secreted by the parafollicular cells of the thyroid gland. The major stimulus of calcitonin production is the serum level of calcium. Calcitonin directly prohibits calcium and phosphate resorption through inhibition of osteoclastic activity, lowering the serum calcium level.

The main regulators of vitamin D synthesis are the serum concentrations of 1,25(OH)₂D₃, calcium, phosphate, and PTH. Vitamin D also can be synthesized through exposure to the sun and conversion in the liver. PTH is the major inducer of the production of the active form of vitamin D in the kidney. This function is accomplished through the effect of the enzyme 1-α-hydroxylase, which transforms the inactive form of vitamin D to the potent form. The active form of vitamin D increases intestinal absorption of calcium and phosphate. Vitamin D also is required for appropriate bone mineralization. The influence of the active form of vitamin D is both a direct effect through stimulating osteoblastic activity and an indirect effect through increasing the intestinal absorption of calcium and phosphorus.

Role of Sex Steroids

The main endocrine function that occurs at menopause is loss of secretion of estrogen and progesterone from the ovaries.^34,46,67 The premenopausal ovary produces primarily estradiol. Progesterone secretion, which occurs cyclically after ovulation in the premenopausal stage, also decreases to very low levels in the postmenopausal stage. These changes in circulating sex steroids are gradual in a woman’s sexual reproductive life. The premenopausal ovary also produces androgens, especially testosterone. The circulating testosterone levels decrease after menopause. The major source of estrogen in postmenopausal women is conversion from dihydroepiandrostenedione. The latter is then converted into androstenedione, which changes into estrone in fat cells. Estrone is the major source of estrogen in postmenopausal women.

Men do not have the equivalent of menopause, but in some elderly men bone mass decreases along with a decline in gonadal function. The testosterone level in men decreases with age as a result of a decreased number of Leydig cells in the testes. Male hypogonadism is typically associated with bone loss.⁴¹

Other Factors Affecting Bone Mass

Several other factors can contribute to the reduction of sex-related steroid levels. In hyperprolactinemia, which is due to a prolactin-secreting pituitary tumor, failure of the gonadal axis results in a substantial loss of bone. Amenorrheic athletes who exercise excessively, such as high-mileage runners or ballet dancers who have lower-than-normal body weight, have lower circulating estradiol, progesterone, and prolactin levels. Their amenorrhea is associated with hypothalamic hypogonadism, which leads to excessive bone loss. This bone loss can be mostly reversed when training distances are decreased.^14,44 With weight gain and improvement in nutrition, these young women can facilitate resumption of menses and reversal of bone loss.^7,21,106 Reduction of sex steroid concentrations is not the only cause of bone loss. Other factors such as race, genetics, nutrition, physical exercise, and lifestyle can also contribute to the rate of bone loss after an ovariectomy or natural menopause.⁷² It is well known that bone must be physically stressed to be maintained. A considerable body of data shows that the rate of change in strain also influences bone growth and remodeling.⁵²

Effect of Aging on Bone Mass

In the normal aging process, there is a deficit between resorption and formation because osteoblastic activity is not equal to osteoclastic activity. The result of the remodeling process is bone loss during each cycle of remodeling. Bone loss occurs even when the remodeling process is not increased. In fact, activation of skeletal remodeling is decreased as a result of the aging process. This decreased activation gives rise to the concept of low-turnover osteoporosis, which occurs concomitantly with the aging process.

Age plays a significant role in the rate of bone turnover. It has been clearly determined that bone turnover increases in women at menopause, but bone turnover does not increase significantly in men with aging. Most studies have shown that plasma levels of the active form of vitamin D—1,25(OH)₂D₃—decrease with age by about 50% in both men and women.

Growth hormone stimulates renal production of 1,25(OH)₂D₃. Growth hormone production decreases with age. Secretion of growth hormone is reduced in patients with osteoporosis. Growth hormone and insulin-like growth factor 1 have several positive effects on calcium homeostasis, including synthesis of 1,25(OH)₂D₃, osteoblast proliferation, osteoclast differentiation, and bone resorption.

It appears that special forms of vitamin K therapy in elderly persons can be associated with a reduction in the rate of bone resorption, demonstrated by decreased excretion of urinary hydroxyproline. Further studies are needed in this area. Studies have shown that calcium absorption is less efficient in elderly people.³² Bone loss also has been related to deficiencies in trace metal elements, such as copper, zinc, and magnesium, but this issue is not fully resolved.

Plasma calcitonin levels are higher in men than in women. Calcitonin levels do not change with age. Studies have shown that estrogens stimulate calcitonin secretion.^99,100 Thyroid hormone levels typically show no change or are slightly decreased with age. The PTH level increases with age, perhaps because of mild hypocalcemia and decreased 1,25(OH)₂D₃ concentration. This reduction in the active form of vitamin D can be due to decreased consumption of dietary vitamin D, decreased exposure to sunlight, decreased skin capacity for vitamin D conversion, reduced intestinal absorption, and reduced 1-α-hydroxylase activity.

Several studies have shown that the level of physical activity decreases with aging.⁷³ This is important because physical strain and mechanical load also positively affect bone mass.²³ Exercise is known to stimulate the release of growth hormone or other trophic factors that can stimulate osteoblastic activity.²⁰ Optimal nutrition and physical activity are necessary to achieve the genetic potential for bone mass. The peak bone mass attained by young adulthood is a major determinant of bone mass in later life. Female gymnasts, both children and college-aged athletes, reportedly have higher BMD than swimmers.^6,19 Nutrition also can affect both bone matrix formation and bone mineralization. In general, in estrogen-deficient women, calcium intake of 1500 mg/day and 800 international units/day of vitamin D are recommended.

Clinical Manifestations of Osteoporosis

Osteoporosis is typically a “silent disease” until fractures occur. Osteoporotic vertebral fractures can go unnoticed until they are incidentally seen on a chest radiograph. Appendicular fractures, however, typically require immediate attention. The fact that a fracture resulted from osteoporosis should not affect the orthopedic method of management. The most common areas for osteoporotic fractures are the midthoracic and upper-lumbar spine (Figure 41-1),⁸¹ hip (proximal femur), and distal forearm (Colles fracture). The highest incidence of fractures is in white women. The female/male ratio is about 7:1 for vertebral fractures, 2:1 for hip fractures, and 5:1 for Colles fractures. It has been estimated that after menopause a woman’s lifetime risk of sustaining an osteoporotic fracture is 1 in 2 or 3.⁵¹

FIGURE 41-1 Incidence of wedging and compression fractures at various levels of the spine.

(Modified from Sinaki M, Mikkelsen BA: Postmenopausal spinal osteoporosis: flexion versus extension exercises, Arch Phys Med Rehabil 65:593-596, 1984, with permission.)

Hip fracture is the greatest concern clinically because the risk of death with osteoporotic hip fracture is 15% to 20%. This is despite all the modern developments in surgical and nonsurgical intervention. The management of an osteoporotic spine fracture requires immobilization of the involved vertebral bodies and analgesia. Fortunately, these fractures heal through becoming more condensed and, unlike appendicular fractures, typically do not require any specific treatment. If there is nonunion of the appendicular fracture, one needs to look for conditions other than osteoporosis, such as osteomalacia or hyperparathyroidism. The duration of immobilization should be for only a limited time, sufficient to ensure the primary fracture-healing process. Prolonged immobilization is discouraged because it can contribute to additional osteoporosis.

The orthopedic management for most osteoporotic fractures is generally noncontroversial, except for the management of hip fracture. The management of femoral neck fracture creates a great deal of controversy because of the high complication rate. Efforts are ongoing to solve these controversies through prospective studies. Despite these efforts, the treatment of hip fracture remains a challenge, and each case creates an emergency situation. Shoulder fracture, especially fracture in the surgical neck of the proximal humerus, is not uncommon in elderly women. This type of fracture usually occurs from an impact force directly to the shoulder during a fall. A conservative treatment regimen typically suffices for this fracture.

Fractures and Management

The relationship between bone mass and spinal fractures has been extensively studied, and it is known that fracture risk increases as bone mass decreases. For every standard deviation of decrease in BMD, the risk of osteoporotic fracture of the spine increases 1.5- to 2-fold, and the risk of hip fracture increases 2.6-fold.³⁰ Another predictor of fracture risk is age itself. The risk of fracture as a result of osteoporosis doubles every 5 to 7 years.³⁰ It is not clear whether age-related changes in bone density or bone quality are factors that increase the risk of fractures caused by falls.

Vertebral Fracture

The incidence of vertebral fractures is poorly understood because 50% of these fractures can be subclinical and the patient might not seek medical attention. Vertebral fractures can create both acute and chronic pain.

Acute pain that occurs in the absence of a previous fracture is usually due to compression fractures of the vertebrae. Sometimes a minor fall or even an affectionate hug can cause a compression fracture. The compressed vertebrae might not be apparent on radiographs for up to 4 weeks after the injury.⁵⁶ Compression fractures usually result in acute pain that later resolves (Box 41-2).⁷¹ The spinal deformity that can result from these fractures can produce chronic pain.⁷¹

BOX 41-2 Management of Acute Pain in Patients With Osteoporosis

Modified from Sinaki M: Metabolic bone disease. In Sinaki M, editor: Basic clinical rehabilitation medicine, ed 2, St Louis, 1993, Mosby. Used with permission of Mayo Foundation for Medical Education and Research.

• Bed rest (2 days): Substantial bone loss is not likely to occur with 2 days of bed rest

• Analgesics: Avoid constipating medicines, such as codeine derivatives

• Avoidance of constipation

• Physical therapy: Initially cold packs, then mild heat and stroking massage

• Avoidance of exertional exercises

• Knowledge of lifting and standing principles to avoid excessive spinal strain

• Back supports if needed to decrease pain and expedite ambulation

• Gait aids if needed

Kyphotic postural change is the most physically disfiguring and psychologically damaging effect of osteoporosis.⁸⁵ The incidence of osteoporosis can be substantially decreased only by early detection and subsequent intervention in high-risk patients.

Disproportionate weakness in back extensor musculature relative to body weight or spinal flexor strength considerably increases the possibility of compressing the vertebrae in the fragile osteoporotic spine. Recognition and improvement of decreased back extensor strength can enhance the ability to maintain proper vertical alignment.⁶⁹ The geriatric population has an increased risk of debilitating postural changes because of several factors, the two most apparent being a greater prevalence of osteoporosis and an involutional loss of functional muscle motor units.^27,50 Development of kyphotic posture not only can predispose to postural back pain but also can increase the risk of falls.⁴⁸ Several other factors also can contribute to the risk for falls (Box 41-3).

BOX 41-3 Factors Contributing to Risk for Falls

Modified from Sinaki M: Falls, fractures, and hip pads, Curr Osteoporos Rep 2:131-137, 2004, with permission.

Extrinsic

• Environmental: Obstacles, slippery floors, uneven surfaces, poor illumination, stairs not well defined, pets, icy sidewalks

• Extraskeletal: Inappropriate footwear, obstructive clothing

Intrinsic

• Intraskeletal: Lower-extremity weakness (neurogenic or myopathic), balance disorder (vestibular dysequilibrium, peripheral neuropathy, hyperkyphosis), visual impairment, bifocals use, vestibular changes, cognitive decline, decreased coordination (cerebellar degeneration), postural changes, imbalance, gait unsteadiness, gait apraxia, reduced muscle strength, reduced flexibility, orthopnea, postural hypotension, cardiovascular deconditioning, iatrogenically reduced alertness

Chronic spinal pain can be due to the deformity caused by vertebral wedging and compression, as well as by secondary ligamentous strain. These deformities are often difficult to distinguish from the usually associated disk deterioration. The intervertebral disks undergo the most dramatic age-related changes of all connective tissues.¹ With aging, there is an increase in the number and diameter of the collagen fibrils in the disk. This change is accompanied by a progressive decrease in disk resilience. Loss of distinction between the nucleus pulposus and the annulus fibrosus eventually occurs.

Chronic back pain secondary to osteoporosis is related to postural changes resulting from vertebral fractures.⁸⁵ Strong back muscles contribute to good posture and skeletal support (Figure 41-2).^33,84,89 One controlled study showed the long-term effects of back extensor resistance training 8 years after cessation of the exercise.^86,91 The women in the study were not receiving hormone replacement therapy. Compared with the exercise group, the control group had a 2.7 times greater number of vertebral fractures at 10-year follow-up evaluation.⁹¹ The pain and skeletal deformity associated with osteoporosis might secondarily reduce muscle strength. The reduction in muscle strength can further exacerbate the postural abnormalities associated with this condition (Figure 41-3).

FIGURE 41-2 Correlation between change in back extensor strength and change in thoracic kyphosis in 29 healthy estrogen-deficient women with hyperkyphosis (≥34.1 degrees). A significant negative correlation was found.

(Modified from Itoi E, Sinaki M: Effect of back-strengthening exercise on posture in healthy women 49 to 65 years of age, Mayo Clin Proc 69:1054-1059, 1994, with permission of Mayo Foundation for Medical Education and Research.)

FIGURE 41-3 At 10-year follow-up evaluation, vertebral compression fractures were found in 14 of 322 vertebral bodies examined (4.3%) in the control group and 6 of 378 vertebral bodies examined (1.6%) in the back extension exercise group (χ2 test, p = 0.029). The number of control subjects with vertebral fractures was 3 times greater in the control group than in the back exercise group.

(Modified from Sinaki M: Critical appraisal of physical rehabilitation measures after osteoporotic vertebral fracture, Osteoporos Int 14:773-779, 2003. Erratum: Osteoporos Int 17(11):1702, 2006, used with permission.)

Chronic pain can also be due to microfractures that are visible only on bone scanning and which can occur continuously. Management of chronic osteoporosis-related pain is outlined in Box 41-4. Prescription of opiate analgesics, such as codeine sulfate or its derivatives, should be undertaken judiciously because their use can cause constipation.⁶⁸

BOX 41-4 Management of Chronic Pain in Patients With Osteoporosis

Modified from Sinaki M: Metabolic bone disease. In Sinaki M, editor: Basic clinical rehabilitation medicine, ed 2, St Louis, 1993, Mosby. Used with permission of Mayo Foundation for Medical Education and Research.

• Improve faulty posture; may need weighted kypho-orthosis.

• Manage pain (ultrasound, massage, or transcutaneous electrical nerve stimulation).

• If cause of pain is beyond correction, apply back support to decrease painful stretch of ligaments.

• Advise the patient to avoid physical activities that exert extreme vertical compression forces on vertebrae.

• Prescribe a patient-specific therapeutic exercise program.

• Start appropriate pharmacologic intervention.

Hip Fracture

Falls and hip fractures can be life threatening.^55,101 In addition to weakness of the lower limbs, one of the contributing factors to falls is disequilibrium of individuals with spinal kyphotic posture.⁷⁸ The kyphotic posture places the center of gravity closer to the limit of stability.⁹³ Measures that reduce instability, such as proper exercise program and use of a weighted kypho-orthosis (WKO), can reduce both the fear of falls and the risk of falls (Figure 41‑4).⁹³

FIGURE 41-4 Composite score of computerized dynamic posturography in control subjects and subjects with osteoporosis-kyphosis at baseline and at follow-up evaluation. Kyphotic subjects improved significantly after a 4-week trial of a spinal proprioceptive extension exercise dynamic program and spinal weighted kypho-orthosis. Data are presented as mean ± standard deviation. A score of 68 or more is normal for ages 60 years or older.

(From Sinaki M, Brey RH, Hughes CA, et al: Significant reduction in risk of falls and back pain in osteoporotic-kyphotic women through a Spinal Proprioceptive Extension Exercise Dynamic (SPEED) program, Mayo Clin Proc 80:849-855, 2005, used with permission of Mayo Foundation for Medical Education and Research.)

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