Bone Cells

Four families of cells combine to create bone tissue that is biomechanically functional and structurally sound. These include the osteoprogenitor cell; its derivative, the osteoblast; the incorporated mature form, the osteocyte; and, finally, the osteoclast. Together, these cells produce new osseous tissue. This tissue is maintained through resorption and remodeling. In short, the cells determine mechanical stability and mineral homeostasis. Healthy bone metabolism results from equilibrating these competing forces. Some forms of metabolic bone disease, therefore, can be viewed as the pathologic imbalance—in number, power, or degree of differentiation—of bone-forming and bone-resorbing cells.^1,2

The osteoprogenitor cells are components of the bone marrow stromal system, approximating the surfaces of bone (periosteum and endosteum) and the adjacent bone marrow environment.³ These potentially mitotic cells, under appropriate stimulation and conditions, give rise to either the bone-forming osteoblast or the cartilage-producing chondroblast. The natural history of these osteoprogenitor cells and the precise signals for their differentiation and modulation are not yet fully elucidated.

Osteoblasts sit on the metabolically active surface of bone in an adherent row, where they synthesize and release unmineralized bone matrix called osteoid.^4–7 They subsequently participate in the mineralization of the osteoid by releasing packets of ions, as well as by synthesizing regulatory and crystal-nucleating noncollagenous proteins. These cells are characterized by high levels of alkaline phosphatase, the ability to manufacture type I collagen and osteocalcin, and the presence of numerous receptor sites for parathyroid hormone (PTH), estrogen, and other products. Osteoblasts are also thought to govern the actions of osteoclasts (described later), thus regulating and coupling bone formation and bone resorption.

The osteocyte, the terminal cell of the osteogenic cell line, is derived from osteoblasts.^4,5 As the osteoblast synthesizes bone matrix, it becomes embedded within its product. The cell is now termed an osteocyte, and the space in which it sits is termed a lacuna. There is one osteocyte per lacuna. Despite being surrounded by bone matrix, the osteocyte communicates with other cells via slender cell processes that it extends for some distance into canaliculi in the surrounding matrix. Thus osteocytes are not completely isolated in their lacunae from other cells but appear to communicate with one another and with surface cells via these cell-to-cell junctions. In this way, osteocytes maintain the matrix that envelops them, regulate local ionic concentrations, and govern the degree of mineralization. In addition, they monitor the local mechanical load and signal changes in the matrix. The surface area covered by the canaliculi is greater than the surface area of osteoblasts and osteocytes combined.

Osteoclasts resorb bone.^8,9 Unlike the mesenchymally derived osteoblast lineage, osteoclasts arise from the monocyte line. These large multinucleated cells are found on the resorbing surfaces of bone, where they bind to a bone-specific integrin¹⁰ and form an isolated macrocavity. At this attachment cavity site, an acidic microenvironment causes the dissolution of the hydroxyapatite mineral and releases acidic proteases that degrade the organic collagen matrix. The resultant resorption cavity is called a Howship lacuna. Thus by remodeling formed bone and delivering calcium into the circulation, the osteoclasts participate in both the mechanical and biochemical roles of bone tissue. Osteoclasts are devoid of PTH receptors, even though they functionally respond to this hormone. Indeed, the hormonal response is found only in those osteoclasts approximated to functional osteoblasts (which do possess PTH receptors). On stimulation by PTH, osteoblasts produce RANKL (receptor activator of NFκB ligand), which interacts with RANK receptors on osteoclast progenitor cells, leading to the activation of mature osteoclasts. Osteoprotegerin (OPG, also known as NFκB) blocks this pathway. RANKL, RANK, and the decoy receptor OPG are the key regulators for the development and activation of mature osteoclasts (Fig. 87–1). Agents that inhibit RANKL via OPG or anti-RANKL antibodies can be used for the treatment of osteopenic disorders such as osteoporosis as well as bone loss associated with bone metastases.^11–14

FIGURE 87–1 The relationship between RANKL, RANK, and the decoy receptor OPG in bone formation and bone resorption. Activated T cells lead to expression of RANKL on osteoblasts by two pathways: (1) They produce cytokines that lead to RANKL expression, and (2) they directly express and produce RANKL. OPG, the decoy receptor for RANKL, blocks both of these pathways. RANKL induces osteoclast formation and activation. Inhibition of RANKL via OPG may prove useful in the pharmacologic treatment of osteopenic disorders including osteoporosis and Paget disease.

(From Theill LE, Boyle WJ, Penninger JM: RANK-Land RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol 20:795-823, 2002.)

Bone Matrix

In addition to the cellular component, two matrices—an organic matrix and an inorganic matrix—constitute the remainder of bone tissue (Fig. 87–2). Whereas the inorganic matrix consists of bone mineral, the organic matrix consists of collagenous fibers embedded in a ground substance.

FIGURE 87–2 Collagen-mineral relationship. The hydroxyapatite forms in the hole zone between collagen molecules.

(From Anatomy II. Orthop. Science. Park Ridge, IL, AAOS, 1986.)

Calcium

Bone exchanges calcium, magnesium, and phosphate and participates in acid-base balance. Of all of these, calcium homeostasis is the most important to both the skeletal and metabolic functions of bone.^27–30 Calcium fulfills its skeletal role in the hydroxyapatite mineral crystal, where it provides mechanical strength. It serves its metabolic function as a free divalent cation. These functions include transducing hormonal signals within the cytoplasm (“second messenger” function), coupling neural excitation with muscular contraction, and effecting homeostasis by interacting with both vascular smooth muscle and platelets.

Body stores of calcium in the typical, 70-kg man total approximately 1300 gm, more than 98% of which resides in the teeth and bones. The remainder is divided between the cytoplasmic and extracellular fluids. The normal serum calcium concentration centers around 9 mg/dL and is found in three states: (1) free (ionized and diffusible); (2) complexed to citrate and other anions (i.e., nonionized but diffusible); and (3) bound to proteins (i.e., neither ionized nor diffusible). Only the free ion (normally about 45% of the total) possesses physiologic activity. At normal body pH, albumin and other anionic proteins bind 50% of the total body calcium. The proportion of protein-bound calcium increases with alkalinity. Accordingly, as the pH rises, the individual becomes effectively hypocalcemic, even though the total amount of calcium, and, importantly, the amount typically reported by standard laboratory tests, remains within normal range. Conversely, in states of liver and kidney failure, when albumin is either not synthesized or lost in the urine, even though the absolute levels of total serum calcium may be depressed, the effective physiologic calcium concentration may be near normal. Calcium-anion complexes account for the remaining 5% of serum calcium. Abnormal levels of these anions may also cause a physiologic calcium disturbance, one not necessarily obvious from the serum calcium concentration. Thus unless ionic calcium is directly measured, attention should be directed at albumin levels and pH state before inferring functional calcium levels from the total serum measurement.

Maintenance of calcium concentration is the responsibility of three organ systems: the gut, to absorb calcium; the bone, to store it; and the kidney, to excrete it. Each of these systems can alter the magnitude of the calcium contribution in response to a number of regulatory substances.

The gut (duodenum and jejunum, specifically) absorbs calcium from the diet, ingested primarily as dairy products. Despite the critical need for calcium absorption, the gut performs this duty with surprising inefficiency: of the recommended daily allowance of 800 mg, only half will ever cross the luminal border, and of that fraction, more than half will be returned to the lumen with the secretion of intestinal fluids. Thus less than one fourth of the daily intake (or only about 150 mg) enters the system.

Active absorption in the duodenum takes place by means of a protein-dependent transport system³¹ that is activated by 1,25-dihydroxyvitamin D (1,25[OH]₂D). In the jejunum, passive diffusion accounts for the remainder of the calcium absorbed. Clearly, the jejunal phase depends more on concentration gradients and intestinal transit times. In addition, dietary composition affects absorption: Diets high in fiber and oxalate (both found in green vegetables) allow for less calcium absorption. In times of increased calcium demand such as the growth years, or during pregnancy, the duodenal fractional absorption can be augmented by increased carrier protein synthesis, which is in turn stimulated by the active vitamin D metabolite (see later). The efficiency of calcium absorption decreases with aging and is adversely affected with bariatric surgery.^29,32

The bone stores calcium. The bone tissue constantly exchanges calcium with the plasma, even when intake matches excretion. This daily, 400-mg exchange results from the nearly balanced remodeling activity of osteoclasts and osteoblasts, as well as the movement of ions between intracellular and extracellular compartments at the osteocyte plasma membrane.

The kidneys are the prime organs of calcium excretion. The glomerular load of calcium is almost 10,000 mg. Most of it is resorbed proximally, following sodium-driven bulk flow. Some calcium remains in the lumen until the distal nephron, where it can be selectively resorbed by calcium-specific transport processes: It follows not only the dictates of calcium-regulating agents but also the demands of salt and water balance and acid-base control. For example, when volume depletion demands increased sodium resorption, proportionally more calcium will be retained proximally, regardless of the serum levels. Diet can also affect renal calcium handling, with both high-protein and high-carbohydrate loads increasing urine calcium excretion. Under normal conditions, the kidneys resorb 98% of the filtered load, with excretion commensurate with intake or resorption from bone. One deleterious consequence of the renal response to high calcium is the formation of stones. Although there is no precise threshold at which stones will form (because other factors, such as urinary flow rate, influence the process) the risk of stone formation increases with hypercalciuria. Most diuretics (with the exception of the thiazides) induce renal calcium loss. Patients with low calcium levels should be evaluated for excessive calcium excretion.

Phosphate

The second important ion in bone metabolism is phosphate.³³ Like calcium, phosphate serves multiple functions throughout the body. As a component of adenosine triphosphate, phosphate participates in the interconversion of the energy of metabolism; as a constituent of nucleotides, phosphate partakes in the transmission and expression of genetic information; and in 2,3-diphosphoglycerate, it regulates the oxygen affinity of hemoglobin.

Phosphate is found in two forms: H₂PO₄⁻ and PO₄³⁻. The ratio of this dissociation, like that of any acid, depends on the pKa of the system, a constant, and the local pH, which can vary. In the extracellular fluid, where the pH is 7.4, the ratio of H₂PO⁴⁻ to PO₄²⁻ is about 4 : 1, whereas in the slightly less alkaline cytosol, the ratio is closer to 2.5 : 1. Unlike calcium, which is physiologically sensed as the free ion, phosphate is internally measured as a sum of both forms. Phosphate’s role outside of bone is also less dependent on concentration; therefore alterations in its level cause few immediate effects. Nevertheless, the quantity of phosphate, normally about 4 mg/dL, is regulated.

The body stores of phosphate sum to 700 gm, about half that of calcium. As with calcium, the majority of it (perhaps 85% of the total) resides in bone. The typical dietary intake is about 1,000 mg/day, of which about two thirds is absorbed. The presence of substances in the gut that can bind phosphate, such as aluminum salts, largely determines the amount of phosphate absorbed. Under normal circumstances, the amount absorbed increases linearly with intake.

As with calcium, the kidney is responsible for maintaining phosphate balance,³⁴ and it does so by a similar mechanism: proximal sodium bulk-driven flow and distal control. When phosphate intake is high, the kidney excretes increasing amounts by spilling the excess phosphate into the urine. When serum phosphate concentrations are low, the kidney can avidly conserve phosphate by implementing vitamin D–mediated changes in calcium concentration. In addition to calcium balance, dietary load, volume status, and acid-base balance also affect renal phosphate handling.

Parathyroid Hormone

Parathyroid hormone is an 84-amino acid polypeptide secreted by the chief cells of the parathyroid glands in response to low serum calcium.³⁵ Its physiologic role is to restore a normal calcium concentration by stimulating all three organs of calcium homeostasis. The kidney and the bone are affected directly,^29,36 whereas the intestine is affected only indirectly, by means of the synthesis of the active vitamin D metabolite 1,25(OH)₂D₃.

PTH promotes calcium conservation in the kidney.³⁷ There, increased serum calcium is achieved through a twofold mechanism; both steps depend on stimulation of adenylate cyclase, the enzyme that forms cyclic adenosine monophosphate (cAMP). First, PTH increases calcium resorption in the distal nephron. In addition, it promotes the loss of phosphate. This phosphaturic effect prevents the recently resorbed calcium from being deposited into the bone hydroxyapatite or into ectopic calcium-phosphate deposits. Moreover, the excretion of phosphate lowers the levels of circulating calcium-anion complexes, causing more of the serum calcium to remain in the physiologically useful, free form.

In the kidney, PTH further promotes elevation of calcium level by stimulating additional synthesis of 1α-hydroxylase, a key enzyme in the formation of active vitamin D, which in turn enhances calcium absorption in the digestive system. In this manner, PTH indirectly affects gut handling of calcium as well.

In the bone, PTH affects calcium metabolism by increasing the surface resorption of the mineral by osteoclasts, by promoting ion flux by osteocytes, and by decreasing their bone synthetic activity through the inhibition of calcium “consumption” by osteoblasts. PTH increases the number of resorptive surfaces in bone and, within them, the density of osteoclasts. The precise mechanism of this osteoclastic action is unfolding and appears dependent on the actions of osteoblasts. The osteoblast does possess PTH receptors. It is postulated that PTH induces the osteoblast to activate the RANKL-RANK system, which stimulates osteoclastic bone resorption. The catabolic effects are reversed by low, intermittent doses of PTH that directly stimulate osteoblastic bone formation but do not activate RANKL.²¹

Vitamin D

Unlike the polypeptide hormone PTH, vitamin D is a steroid.³⁶ As such, it defies rapid proteolytic inactivation and thus functions best as a longer-acting regulator of calcium homeostasis. The principal effect of this hormone is to increase intestinal absorption of calcium from the diet, a process that is usually only 25% efficient. Secondarily, it complements PTH in the promotion of calcium resorption from the bone, again by promoting transport across cell membranes (in this case, bone cells rather than intestinal cells).

Cholecalciferol (inactive vitamin D₃) forms in the skin from the ultraviolet light activation of 7-dehydrocholesterol, an intermediate of cholesterol synthesis.³⁸ 7-Dehydrocholesterol can degrade and re-form cholecalciferol; therefore once formed, cholecalciferol is removed from the local environment by a transport protein, thus favoring further formation. As little as 15 minutes of sunlight exposure allows the synthesis of a fair-skinned individual’s vitamin D₃ requirement. The total need for sunlight increases with melanin concentration. In the absence of sun exposure, cod liver oil and enriched milk and cereals can provide usable precursors of the hormone.

In the liver, vitamin D₃ undergoes 25-hydroxylation,³⁹ forming the prehormone 25-hydroxyvitamin D (25[OH]D). Subsequent 1-hydroxylation to the active form, 1,25(OH)₂D₃, takes place in the kidney and is promoted by PTH. In the presence of low PTH, an alternative hydroxylation occurs at the 24 position, yielding 24,25(OH)₂D₃, an inactive form of the hormone. Unlike PTH, which is functionally regulated at the level of secretion (calcium levels do not cause minute-to-minute changes in messenger RNA activity but rather control the release of PTH), vitamin D is regulated at the level of biosynthesis. The 1-hydroxylation reaction is the rate-limiting step and is regulated by feedback inhibition, as well as by PTH levels.

Active vitamin D, also known as calcitriol, promotes increased transport across cell borders. As a steroid maturation hormone, vitamin D works by crossing the cell membrane and subsequently entering the nucleus. There it binds to DNA to promote DNA translation, thus increasing the synthesis of the target proteins. Vitamin D mediates increased expression of calcium-transport proteins, although the nucleic receptor has not yet been identified. In the gut, 1,25(OH)₂D₃ causes increased calcium transport; phosphate absorption increases as well. In the bone, 1,25(OH)₂D₃ complements the action of PTH by increasing calcium transport across bone cell membranes, thus assisting with the mobilization of calcium from the bone and into the circulation. As such, it functions as an agent of bone resorption. It can indirectly assist with bone formation as well because the tasks of mineral homeostasis and skeletal homeostasis are not always at odds with each other. Calcium needs can usually be met through the diet, not by bone resorption. Vitamin D also functions as a maturation hormone by increasing the villous membrane of the gut and augmenting PTH recruitment of macrophage stem cells, the bone-resorbing osteoclast precursors. Accordingly, vitamin D, which promotes the uptake of dietary calcium, typically also serves as an agent of bone maintenance. In addition, vitamin D has been associated with decreased cancer rates, improved muscle function, and a more normal immune system.⁴⁰

Calcitonin

Calcitonin is a 32-amino acid polypeptide secreted by the parafollicular cells in the thyroid in response to increased serum calcium concentration. Calcitonin lowers serum calcium levels by its actions in the bone and the kidney. Still, its precise physiologic role awaits determination.^41,42

In the bone, calcitonin rapidly inhibits osteoclastic action at pharmacologic doses. Direct calcitonin-binding sites are present on osteoclasts. Calcitonin decreases the number and activity of osteoclasts. Specifically, it decreases the adherence of osteoclasts to bone resorptive surfaces and diminishes their activity once they adhere. Calcitonin also affects osteocytes, causing decreased calcium ion flux across their cell membranes. In the kidney, calcitonin blocks the reuptake from the glomerular fluid of calcium and phosphate, as well as that of other ions, notably sodium (which influences calcium uptake by the passive mechanisms described earlier). Calcitonin may also influence calcium handling in the gut and, at pharmacologic doses, may alter other intestinal processes (such as water balance).⁴³

High levels of calcitonin may cause transient hypocalcemia, without causing any residual skeletal effects. In patients with medullary carcinoma of the thyroid (a malignancy of the parafollicular cells), calcitonin levels are several orders of magnitude higher than in healthy patients. Nevertheless, such patients demonstrate neither long-term derangements of calcium metabolism nor loss of skeletal integrity. Furthermore, patients who have had a complete thyroidectomy, and are thus completely calcitonin deficient, show no persistent hypercalcemia. Both examples bolster the hypothesis of a small physiologic role for calcitonin.

Despite a perhaps minor physiologic role, calcitonin is important medically. First, in patients with medullary carcinoma of the thyroid, measurement of serum calcitonin level provides an assessment of tumor burden. Calcitonin levels can be measured as a screening test in those patients at risk for medullary carcinoma, namely, relatives of patients with multiple endocrine neoplasia type II. Finally, calcitonin (most often as a salmon-derived analogue) is also used as a drug to inhibit osteoclasts, as in Paget disease and osteoporosis, or to quell the hypercalcemia accompanying a variety of malignancies. In addition, it has analgesic properties that enhance its therapeutic use.

Pathology

Osteoporosis is a disease of decreased bone mass in the absence of a mineralization defect. Bone mass is diminished; however, the bone that remains contains a normal matrix and a normal degree of calcification. Declining bone mass is now thought to be a universal phenomenon of aging.⁵⁸ Peak bone mass is attained in the mid 30s for both sexes. Gender, nutrition, race, exercise habits, and overall health all influence bone mass. Peak bone mass is higher in men than in women and higher in African Americans than in whites.⁵⁹ After the fourth decade, both men and women lose bone mass from the skeleton (Fig. 87–3). Two phases of this loss have been identified: slow and accelerated. The slow phase, related to an imbalance between resorption and formation leading to negative calcium balance, is equal in both men and women. It results in an annual basal slow phase rate of bone loss of 0.3% to 0.5%.⁶⁰ The accelerated phase that occurs with estrogen deficiency—a phenomenon found exclusively in women—is responsible for cortical bone mass loss of 2% to 3% per year. This loss is in addition to the slow phase losses, which continue during the accelerated phase. The accelerated phase begins after surgical or natural menopause and lasts for approximately 5 years.⁶⁰ Thereafter, bone loss continues at the basal slow phase rate.

FIGURE 87–3 Bone mass as a function of age in men and women.

(From Disorders of Bone 9. Orthop. Science. Park Ridge, IL, AAOS, 1986.)

Multiple studies have shown the importance of estrogen deficiency in the causation of the accelerated phase.^61,62 Estrogen is thought to play a critical role in maintaining bone mass in adult women by suppressing cancellous bone remodeling and maintaining remodeling balance between osteoblastic and osteoclastic activity. With estrogen deficiency, there is increased osteoclastic activity and possibly also impaired osteoblastic activity, resulting in a remodeling imbalance.⁶³ The administration of estrogen to women during this period of rapid bone loss can decrease the loss in all bones, especially those rich in trabecular bone (e.g., the vertebral bodies, the pelvis and other flat bones, in the ends of long bones).⁶⁴

Riggs and Melton⁶⁰ have subclassified primary osteoporosis on the basis of patterns of bone loss and fracture (Table 87–1). Type I or “postmenopausal” osteoporosis primarily affects trabecular bone sites and is characterized by fractures of the vertebral bodies and wrist. In patients with type I osteoporosis, the rate of trabecular bone loss is three times above normal but the rate of cortical bone loss is only slightly above normal. In contrast, type II osteoporosis, also known as “senile” osteoporosis, occurs in both men and women aged 75 years and older and involves areas of predominantly cortical bone. Clinically, fractures of the hip, pelvis, proximal humerus, and proximal tibia are seen. The causes of senile osteoporosis are the aging process itself and chronic calcium deficiency. Senile osteoporosis may also involve decreased vitamin D and increased PTH activity or impaired bone formation. Osteoporosis in patients between the ages of 66 and 74 years may represent a combination of these two syndromes.

TABLE 87–1 Type I versus Type II Osteoporosis

From Riggs BL, Melton LJ 3rd: Evidence for two distinct syndromes of involutional osteoporosis. Am J Med 75:899, 1983.

The spine is composed of primarily trabecular bone. Compared with cortical bone, it has a high surface-to-volume ratio. Because metabolic activity (remodeling) occurs on bone surfaces, trabecular bones in general, and the vertebral bodies in particular, are resorbed preferentially in times of skeletal loss.⁶⁵ Osteoporosis is thus characterized by trabeculae of decreased size and number. Work by Dempster and colleagues⁶⁶ has demonstrated that osteoporosis involves a thinning of the cortex, as well as a change in the shape of the trabecular bone from plates to narrow bars. The trabecular bone contains areas in which osteoclasts create a loss of connectivity, leading to a significant and localized weakening of the bone.^66,67 Vertebral body density declines before a similar loss is detected in cortical areas.

The body accommodates bone loss by redistribution. As people grow older, the diameter of the long bones gradually increases in both women and in men. Concurrently, the medullary diameter also increases, leading to a net thinning of the cortical bone. A 10% shift of bone mass outward from the epicenter through an enlargement of the bone diameter will compensate for a 30% decrease in the bone mass against applied bending and torque stresses but not against axial loading. This differential resorption explains the timing and patterns of the fracture syndromes seen in osteoporosis.⁴⁶ The incidence of vertebral compression fractures rises immediately after menopause, whereas the hip (with its higher proportion of cortical bone) fractures later in life, when cortical bone loss accumulates over the next 1 to 2 decades. The distal forearm, like the spine, has high trabecular content, so the incidence of Colles fractures also increases in menopause.

Deficiencies in dietary calcium cause decreased peak bone mass.⁶⁸ White women on average have less bone than either white men or African Americans of either sex.⁶⁹ Thus the risk of clinically significant osteoporosis depends on hereditary factors, gender, race, and nutrition, which all contribute to peak bone mass, and aging, which causes progressive bone loss. Although the formation of good bone in sufficient quantity in young adulthood is clearly important, the aging process remains the most important cause of involutional osteoporosis.

Aging leads to bone loss independent of menopause, but the rapid decline of skeletal mass after estrogen deficiency implies that this hormone prevents the dissolution of the skeleton.⁷⁰ Nonetheless, its precise mechanism is unclear. Some investigators believe that the action is mediated by estrogen receptors on osteoblasts.⁷¹ Others contend that estrogen antagonizes PTH activity⁷² or stimulates endogenous calcitonin release. Decreased calcitonin levels have been found in oophorectomized and postmenopausal patients, and increased calcitonin levels are noted after estrogen administration. Regardless of the mechanism, estrogen deficiency leads to bone loss and plays a major role in the pathogenesis of type I osteoporosis.

The age-related (“slow phase”) bone loss is not affected by estrogen; rather, it likely represents impaired vitamin D metabolism. As an individual ages, the kidney gradually loses its ability to hydroxylate vitamin D into its active form, 1,25(OH)2D.⁷³ This active vitamin D is necessary to transport calcium in the gut; therefore decreased hydroxylation, often coupled with poor dietary intake, leads to lowered serum calcium levels and, in turn, to elevated secretion of PTH. In addition to secondary hyperparathyroidism, elderly people are also more likely to take medications (e.g., diuretics) that further contribute to calcium losses. Furthermore, there is some evidence that the mechanism in remodeling that couples the actions of osteoclasts and osteoblasts functions suboptimally in old age: after the fourth decade, at a given site of remodeling, less bone is laid down than is resorbed.⁶⁹ Accordingly, normal bone turnover in the elderly leads to calcium depletion as well.

Clinical Course

End-stage osteoporosis culminates in fracture.^27,29,74 Still, for most of its course osteoporosis is a silently progressive disease. Patients typically present to the physician, usually late in the course, following one of three general scenarios. In the first of these, the patient presents with an acute painful fracture, usually of the spine (Fig. 87–4), but possibly of the rib, wrist, or hip. In the spine, normal activity (even minimal activity) may exceed the depleted bones’ stress tolerance and result in fracture. The acute fracture can be severely painful, with the pain remaining over the affected area or radiating across the thorax. The pain from a vertebral fracture does not radiate down the legs. Symptoms such as leg pain suggest involvement of the spinal cord and obligate the physician to search for another or concomitant process to explain the pain. Osteoporosis, even if established in such a case, is probably not the only disease present. The acute pain usually abates when the fracture heals. Nonetheless, the patient rarely returns to the prefracture status. At a minimum, there may be point tenderness over the fracture site. The patient may note constant abdominal pain, often brought about by the constraining forces on the viscera in the now smaller abdominal cavity. Other patients complain of generalized backache. The backache may be due to changing muscular demands brought on by altered spinal curvature. Furthermore, some patients fear reinjury and strictly limit their activities. Others develop chronic pain syndromes, dysthymic states, or even overt clinical depression. Osteoporosis, therefore, often has a profound effect beyond the acute fracture episode.

FIGURE 87–4 Lateral radiograph of the lumbar spine showing vertebral compression fractures at L1 and L2 levels (arrowheads).

Not every patient has an acute episode. In an alternate scenario, an asymptomatic thoracic wedge or lumbar compression fracture of the spine may be noted on a radiographic examination performed for an unrelated purpose. These compression fractures may present subacutely, with twinge pain noted on minimal strain or exercise over a period of time, or the patient may even have no complaints at all. The macroscopic fracture observed on radiography, then, represents integration over time of a series of small, individually insignificant microfractures.

In the thoracic spine, both asymptomatic and painful fractures have a predilection for the anterior aspect of the bone. Progressive fracture thus leads to progressive shortening of the anterior height of the vertebral body relative to the posterior. The resultant shape of the body suggests the name of this process: wedge fracture. The wedge shape of the body, when summed over two or more vertebrae, causes dorsal kyphosis. In the lumbar region, the fractures are usually distributed equally throughout the vertebral body. No wedge is formed in this situation, and the process is thus termed compression or collapse fracture. The combined effects of compression and wedge fractures lead to an unfortunate, but common, skeletal deformity: lost height coupled with excessive dorsal kyphosis. A vertebral body deformation due to an osteoporotic fracture can be difficult to determine.

Finally, generalized osteopenia without fracture may be noted on plain radiographs. This is not a different disease but, rather, an earlier phase of the same process that leads to fracture and deformity. These patients suffer from bone loss but have not yet crossed the critical point of stress tolerance.

Diagnosis

While a good clinical understanding of osteoporosis takes into account the pathophysiology of bone remodeling, mineralization changes, and variable bone quality of the patient, the diagnosis of osteoporosis until recently has relied on a single criterion: the bone mineral density. Bone mineral density testing is currently the clinical standard for diagnosing osteoporosis. Bone mineral density is the best predictor of osteoporotic fractures in postmenopausal women because bone mass accounts for approximately 60% to 80% of bone strength.^75–77 Bone mineral density testing offers a painless and noninvasive way to identify osteoporosis, predict a patient’s risk for fractures, and monitor treatment.

The World Health Organization (WHO) definition of osteoporosis is expressed in terms of the T score, defined as the number of standard deviations below the peak adult bone mass of young healthy adults (Table 87–2). Individuals whose T score is within 1 SD of the mean (T score ≥ −1) are considered to have normal bone density. Individuals with osteopenia have T scores that fall between 1 and 2.5 SD below the mean (T score < −1 but > −2.5). An individual with a T score that is at or below –2.5, or 2.5 SD or more below the average peak density of a young adult, is considered to have osteoporosis. Severe osteoporosis defines an individual with bone density that is 2.5 SD or more below the average peak of a young adult in the presence of one or more fragility fractures. In addition, a patient may fracture without “osteoporotic” bone by bone density levels. The WHO set a standard with definitions of “osteopenia” and “osteoporosis,” defining the latter as low bone density with increased fracture risk.

TABLE 87–2 Definition of Osteoporosis Based on Total Hip Bone Mass Density

SD, standard deviation.

Adapted from Kanis JA, Glüer CC: An update on the diagnosis and assessment of osteoporosis with densitometry. Committee of Scientific Advisors, International Osteoporosis Foundation. Osteoporos Int 11:192-202, 2000.

The Z score compares a patient’s bone mineral density to a reference population of the same age, sex, and ethnicity fracture. The Z score indicates how many standard deviations the patient’s bone mass density is below the expected value for his or her own age. The Z score cannot be used to diagnose osteoporosis, but it is useful for screening the patient for secondary causes. A Z score of −1.5 or lower should increase the index of suspicion that underlying medical problems, medications, or other factors may be responsible for the patient’s low bone mass density.⁷⁸

Although several tests are available to measure bone mineral density, dual-energy x-ray absorptiometry (DEXA) is the technical standard. DEXA is the preferred technique because it measures bone mineral density at the important core sites of osteoporotic fractures including the hip and spine. The WHO has reported that a measurement at either the total hip or femoral neck is preferred, but that posteroanterior (not lateral) vertebral bone mineral density can be used to make the diagnosis.⁷⁴

The spine is a useful site for bone mineral density measurement because it predicts the risk of any fracture as well as or better than hip bone mineral density in the perimenopausal population in which hip fracture risk is low. With advancing age, however, spine measurements are confounded by osteoarthritis and soft tissue calcification to a greater degree than the hip.^79,80 For this reason, the hip is the preferred site, especially in women older than 60. Based on the WHO diagnostic threshold, 15% to 20% of postmenopausal women can be identified as having osteoporosis when measurements using DEXA are made at the spine or hip.⁷⁴

A number of risk factors for osteoporosis have been identified by the International Society for Clinical Densitometry (ISCD)⁸¹ and should be used to guide the screening process in a cost-effective manner. The current indications for bone mineral density testing include any patient who is:

In addition to these guidelines, it is important to take into account other factors that may increase a patient’s propensity for low bone mineral density or fracture. Patients with poor general health, alcoholism, dementia, frailty, recent discontinuation of estrogen replacement therapy, or long-term history of estrogen deficiency should be considered for DEXA scanning even if they do not fit into the ISCD criteria.

Adapted from Camacho P: Biochemical markers of bone turnover. In Favus MJ (ed): Primer on the metabolic bone diseases and disorders of mineral metabolism, 6th ed, Washington, DC, American Society for Bone and Mineral Research, 2006, p. 127.

During bone formation, osteoblasts produce type I collagen, which is their major synthetic product. Carboxy-terminal propeptide and amino-terminal propeptide of type I collagen, known as PICP and PINP respectively, are cleaved from the newly formed collagen molecule and therefore can be used as the indices to indicate type I collagen biosynthesis. Osteoblasts also secrete a variety of noncollagenous proteins, two of which are used clinically as markers of osteoblast activity: bone specific alkaline phosphatase and osteocalcin. It is these noncollagenous products that are most useful as markers for bone formation. Although alkaline phosphatase is derived from several tissues, the two most common sources are from liver and bone. The utilization of tissue-specific monoclonal antibodies is able to differentiate between liver and bone isoform; however, the bone isoform has 10% to 20% cross-reactivity with the liver isoform.⁸³

During osteoclast-mediated bone resorption, the collagen structure within bone is degraded. This collagen degradation product is used as an indicator for bone resorption. In general, collagen molecules in bone matrix are staggered to form collagen fibrils by covalent cross-links.⁸⁴ These cross-links consist of pyridinolines (Pyds) and deoxypyridinolines (Dpds). Pyd and Dpd cross-links occur at two intermolecular sites in collagen molecule: amino-terminal-telopeptide and carboxy-terminal-telopeptide. As part of this degradation process, cross-linked collagen peptides from both the amino-terminal-telopeptide (NTX) and carboxy-terminal-telopeptide (CTX) are released and achieve measurable concentrations in both serum and urine. Therefore when osteoclasts resorb bone, they release a variety of collagen breakdown products into the circulation that are further metabolized by liver and kidney. These include free Pyds, free Dpds, NTX, and CTX.

Despite the popularity of urine NTX, there are limitations to its use as a dynamic measure of bone resorption. As with other urine biochemical bone markers, NTX must be normalized for creatinine clearance. The urine assay loses reliability with impaired renal function, and the serum markers are then preferred. Biochemical bone markers are also subject to technical and biologic variability. Unlike bone mineral density measurements for osteopenia and osteoporosis, there are currently no accepted criteria for what constitutes a high turnover rate.

The use of bone biochemical markers to determine therapy effectiveness is their best established clinical use. Several studies indicate that, within 4 to 6 weeks, there is significant reduction in biochemical markers of bone resorption after initiation of antiresorptive therapy.^85–87 Lack of marker reduction may indicate noncompliance or the need to change the dosage or the therapeutic agent. Serial bone mineral density tests should be at least 12 (and possibly 24) months apart; therefore more frequent measurements of biochemical markers offer a significant advantage.

Evaluation for Secondary Osteoporosis

When secondary osteoporosis is suspected on the basis of clinical findings or because the patient is relatively young and presented with fragility fracture, specific tests should be considered to evaluate contributing causes that may require additional medical attention. These include basic laboratory investigation of a complete blood count with differential, erythrocyte sedimentation rate, serum calcium and phosphate levels, liver function tests, thyroid-stimulating hormone level, testosterone level in men, and a serum protein electrophoresis if myeloma is considered (Table 87–4). When abnormalities are detected, the patient should be referred to a specialist for further evaluation and specific treatment.

TABLE 87–4 Laboratory Investigations for Secondary Osteoporosis

Nutrition, Calcium, and Vitamin D Supplementation

First-line treatment of osteoporosis includes adequate dietary intake of calories, protein, calcium, and vitamin D. Calcium and vitamin D supplementation is the cornerstone of all treatment modalities for osteoporosis. Literature clearly showed that adequate calcium and vitamin D intake reduced the risk of fractures. For optimal treatment, adequate calcium intake of 1000 to 1500 mg/day should be maintained in all patients on any type of treatment.^93,94 To maximize the absorption of calcium across the small bowels, no more than 500 to 600 mg of elemental calcium should be taken at any given time.⁹⁵ Among all calcium formulations, calcium citrate is the preferred form. Calcium citrate binds to oxalate, reducing its intestinal absorption, and citrate in urine inhibits crystal formation, thus reducing the incidence of kidney stones. In addition, calcium citrate does not require low pH for salt dissociation; therefore the absorption of this calcium formulation is reliable in patients taking H₂ blockers or proton pump inhibitors.⁹⁶

The current recommended dosages of vitamin D₃ from the Institute of Medicine are 200 to 600 IU/day.⁹³ However, many experts consider these recommendations to be too low and suggest that the minimum adult intake should be 1000 to 2000 IU/day.⁹⁷ The appropriate amount of vitamin D intake should be evaluated by monitoring 25 (OH) D level and serum PTH. Patients with vitamin D insufficiency will have low levels of 25 (OH) D and elevated serum PTH from secondary hyperparathyroidism. Higher doses of vitamin D are required in these patients to replenish depleted total body stores. Fifty thousand international units of vitamin D₂ (ergocalciferol) can be taken orally once a week or every other week for 6 to 8 weeks, followed by a maintenance dose of vitamin D₃ of 1000 to 2000 IU/day. Toxicity is rare even if a dosage of 10,000 IU/day is given for up to 5 months.⁹⁸

Protein is also a significant contributor to bone health. A randomized prospective study that studied hip fractures in 82 elderly women demonstrated that those who took protein supplementation in addition to calcium and vitamin D supplements had an attenuation of the loss of bone at 1 year compared with those who received nonprotein supplements.⁹⁹ However, high dietary protein and sodium increase urinary calcium excretion and have also been shown to decrease the calcium available to the skeleton.¹⁰⁰

Exercise

Regular physical activity reduces the risk for osteoporosis and osteoporotic fractures.^101,102 Weight-bearing exercise has beneficial effects on bone mineral density including that of the spine in both premenopausal and postmenopausal women.^{101,103–106} In one study, young women (aged 20 to 35) were randomized into groups of exercise and calcium supplementation for 2 years and bone density at various sites was evaluated. The group randomized to the aerobics and weight-training program had a 2.5% increase in their spine density compared with the calcium and stretching program.¹⁰⁷ Muscle mass is significantly correlated to bone mass,²⁹ suggesting that increased skeletal loading leads to increased bone mass. In a study of postmenopausal women, strength training increased bone density in both the spine and hip, whereas inactivity decreased bone density at both sites after just 1 year.¹⁰¹ As little as 1 hour of exercise two or three times per week can increase vertebral bone mass in postmenopausal women, whereas inactivity results in continued bone loss and increased risk for hip fracture.¹⁰⁸

Immobilization results in decreased bone mass through increased activation at remodeling sites and decreased osteoblast stimulation.¹⁰⁹ Bone loss with complete immobilization can reach 40% in 1 year but can be prevented with upright positioning and daily postural shifting for 30 minutes.¹¹⁰ Permanent bone loss can be prevented by instituting exercise within the first months of immobilization.¹⁰⁹ Therefore although the gains in bone mass with exercise may be small, the decline in bone mass and subsequent increased fracture risk with inactivity can be substantial and irreversible.

Regular physical activity also improves muscle strength and balance, thus reducing the risk of falls.^111–114 An exercise program of tai chi, combining traditional Chinese medicine and martial arts and performed while standing, significantly improves balance,¹¹⁵ mitigates the fear of falling, and reduces falls in the elderly by more than 47%.¹¹¹

Conservative management of osteoporotic patients should include an exercise program to minimize the effects of a more sedentary lifestyle common in elderly. The prescribing physician should tailor the exercise regimen to the patient’s overall fitness, most specifically the cardiac tolerance. Accordingly, exercises that deliver high impact for a given aerobic effort such as walking are preferable to those such as swimming that have less effect. Nevertheless, general muscle strengthening therapy prevents falls.

A comprehensive general rehabilitation program that stresses spine extension and abdominal strengthening exercises without flexion, as well as impact-loading activities such as walking, should be part of the treatment plan for every osteoporotic patient. Persistent participation in the exercise program is important because the benefits of exercise are quickly lost with cessation of the exercise regimen.¹⁰⁵

Pharmacologic Treatment

Osteoporosis has been divided into high-turnover and low-turnover osteoporosis. The pharmacologic agents currently available are commonly divided into two groups: antiresorptive and anabolic. Antiresorptive agents have been developed to address the high-turnover state. These include estrogen, selective estrogen receptor modulators (SERMs), calcitonin, and bisphosphonates. The anabolic agent, parathyroid hormone, provides active building of bone mass and has been suggested to treat the low-turnover state. Both antiresorptive and anabolic agents have demonstrated antifracture efficacy in many studies.

Antiresorptive Agents

Anabolic Agents

Teriparatide, parathyroid hormone (1-34), is the only anabolic agent available for the treatment of postmenopausal osteoporosis in the United States. It is administered subcutaneously once a day. When given intermittently, teriparatide can increase bone mass up to 13% over 2 years of therapy.¹³⁹ This increase is greater than that achieved with bisphosphonate therapy. The risk of fracture was reduced by 65% and 53% for vertebral and nonvertebral fracture, respectively.¹⁴⁰ Other benefits of teriparatide have been proposed. Many studies reported the possible benefits of teriparatide on fracture healing. Callus formation was accelerated by the early stimulation of proliferation and differentiation of osteoprogenitor cells and increases in production of bone matrix proteins. Teriparatide should be considered in these conditions:

Contraindications include active Paget disease of bone, unexplained elevations of alkaline phosphatase, history of skeletal irradiation, and children with open epiphyses. The adverse reactions associated with teriparatide are nausea, headache, dizziness, leg cramps, swelling, pain, weakness, erythema around the injection site, and elevation of serum calcium. There is a concern regarding osteosarcoma due to evidence showing that rodents, exposed to prolonged high doses of teriparatide, developed osteosarcoma.^141,142 Therefore teriparatide should be discontinued after 2 years of treatment. After that, bisphosphonate therapy should be initiated to maintain its results.

Pharmacologic Agents and Spinal Fusion

No clinical studies have evaluated pharmacologic agents for osteoporosis in the setting of vertebral fractures or spinal fusion. Bisphosphonates increase fracture callus size during endochondral repair but cause delay in maturation.¹⁴³ Animal studies in rats and rabbits have clearly demonstrated that bisphosphonates delayed, and at higher doses prevented, spinal fusion.^144,145 Therefore bisphosphonates should not be used following spinal fusion or acute vertebral fracture in order to reduce the possible adverse effects to the early biologic processes of fracture healing. Teriparatide in all animal studies assisted fracture healing. In both rat and rabbit models of spinal fusion, the administration of teriparatide significantly enhanced fusion and increased the fusion mass.^146,147 On the basis of these animal studies, teriparatide offers superior biology for spinal indications, when compared with bisphosphonates and controls that only took calcium and vitamin D. The application of this agent in patients, however, still awaits evidence-based studies.

Strategies for Treatment of Osteoporosis Spine Patient

In general, the program for spinal care in elderly patients, particularly with osteopenia/osteoporosis, includes a thorough medical history and physical examination, appropriate diagnostic tests, maintenance of adequate nutrition including calcium, vitamin D, and the utilization of appropriate osteoporotic therapeutic agents. The pharmacologic approach to the osteoporotic spine patient should be individualized on the basis of that patient’s bone physiology. High- versus low-turnover states can be assessed from levels of biochemical bone markers. Patients identified with high-turnover osteoporosis are most effectively treated with antiresorptive agents to address the inappropriately high osteoclastic activity. Conversely, patients with low-turnover osteoporosis should be considered for an anabolic agent that actively builds new bone. If the patient plans to have spinal surgery, he or she should stop antiresorptive medications until evidence of spinal fusion is obtained. On the other hand, in the setting of spinal fusion and fracture healing, an anabolic agent such as parathyroid hormone may be advantageous in the early steps to enhance appropriate biologic responses.

Future Directions

The available pharmacologic agents used to treat osteoporosis have their own limitations. Understanding of cellular mechanisms regulating bone formation and remodeling is critically important for developing new agents that will reduce the adverse effects or improve the outcome of treatment. Denosumab, a human monoclonal antibody against RANKL, has been shown in preclinical trials to increase bone mineral density and decrease bone resorption in postmenopausal women with osteoporosis.^12–14 It is now approved by the FDA for the treatment of postmenopausal osteoporosis. Cathepsin-K inhibitors are another group of antiresorptive agents, which were designed to reduce the activity of cathepsin K (a powerful osteoclast protease). Theoretically, this agent can limit the enzymatic degradation of bone matrix proteins. It is currently approved in Europe but not in the United States.¹⁴⁸

Strontium ranelate is an agent that has both antiresorptive and anabolic action. Treatment of postmenopausal osteoporotic women with strontium ranelate has been shown to decrease fracture risk and increase bone mineral density.^149,150 The long-term effects, however, remain unknown. The development of new formulations of teriparatide (noninjectable forms) or development of alternative parathyroid hormone analogs that possess longer half-life, leading to less frequent dosing, are also under investigation.^151,152

Pathology

Paget disease is a focal disorder of accelerated skeletal remodeling that usually involves a single bone (monostotic) or several bones (polyostotic) and rarely affects numerous bones. Initially, there is an increase in the rate of bone resorption at areas of bone remodeling (Fig. 87–5). Pagetic osteoclasts are abnormal in several ways: They are greater in size and number and highly multinucleate, with up to 100 nuclei.^159,160 In response to this increased resorptive activity, additional osteoblasts are recruited to remodeling sites, with increased production of qualitatively poor new bone matrix that is deposited in a disorganized woven pattern. The result is increased bone formation and a disruption of the normally organized lamellar collagen architecture.¹⁵⁹ Over time this woven bone is incompletely replaced by more organized bone as is the case with a fracture callus.

FIGURE 87–5 Histologic appearance of Paget disease. A, Mosaic pattern. B, Polarized view of disorganized collagen.

(From Disorders of Bone 20. Orthop. Science. Park Ridge, IL, AAOS, 1986.)

The etiology of Paget disease remains unknown. Evidence exists for both viral and hereditary causes. Genetic factors seem to play a role as evidence by the epidemiology of British migrants being affected more frequently. Familial clusters of Paget disease have been documented.^158,161 A positive family history has been reported in up to 40% of patients.¹⁵⁶ A first-degree relative has 7 times greater risk of developing Paget disease.¹⁶¹ Genetic studies have identified several possible loci for Paget disease.^162–164 Sequestosome 1 (SQSTM1) is the best studied and encodes for a scaffold protein (p62) in the nuclear factor κB (NFκB) signaling pathway.¹⁶⁵ The common area of interruption is the region encoding the binding site for ubiquitin. The loss of the ubiquitin site leads to disregulation of the protein, which is thought to lead to activation of the RANKL pathway and subsequent increased osteoclast activity.¹⁶⁵

Environmental factors also may play a role in Paget disease. Initial enthusiasm for a viral etiology was stimulated by the nuclear and cytoplasmic inclusion bodies, similar to paramyxovirus nucleocapsids, detected in affected osteoclasts by numerous methods in several studies.^166–169 Several syncytial viruses and canine distemper virus have also been postulated to play a role in the etiology of Paget disease.^166,170 A characteristic feature of these viruses is their ability to persist at low levels and invade the host immune system.

Despite decades of research, a pure viral cause for Paget disease has not been proven. No virus has ever been cultured from Pagetic cells. PCR studies have had mixed results attempting to isolate measles virus and canine distemper virus from blood and osteoblasts of patients with the disease.^171,172 Also, unlike the distinctive geographic distribution of Paget disease, measles has a similar incidence worldwide and occurs in young patients, whereas Paget disease generally occurs in the elderly.¹⁷³ Furthermore, similar viral nuclear inclusion bodies have been identified in other skeletal disorders, so the virus may be a nonetiologic cotraveler in an osteoclast altered by some other mechanism.

Clinical Course

Most patients with Paget disease are asymptomatic. The disease is often detected when the patient has a radiograph taken or serum alkaline phosphatase measured for an unrelated reason. In the majority of patients with Paget disease, one or several bones are involved. In decreasing order, the most commonly involved bones include the pelvis, lumbar spine, femur, thoracic spine, skull, tibia, humerus, and cervical spine; however, any bone may be affected. The lumbar, thoracic and cervical vertebrae are affected in 58%, 45%, and 14% of patients, respectively.^174,175

Clinical manifestations, when present, cover a wide spectrum. Patients who are symptomatic most often present with back pain,¹⁷⁶ although other areas, especially the hip, can be involved. The skull can be implicated in the disease, and when it is the woven bone expansion can encroach on the cranial nerves, most typically the eighth nerve. Both the acoustic and the vestibular branches can be affected; hence the initial presentation of Paget disease might be decreased hearing or difficulty with gait or balance.¹⁷⁵

In the spine, the pain is infrequently due to primary Pagetic involvement alone but rather represents related secondary changes (Fig. 87–6).¹⁷⁷ These include osteoarthritis of the spinal facets; encroachment on the spinal cord; or in the case of intense pain, pathologic fracture. When the spinal column is involved, most often it is the thoracolumbar regions that are affected but cervical disease may also contribute.¹⁷⁸ Involvement of the spinal cord may be secondary to a mechanical or vascular complication. Of the mechanical causes, vertebral collapse, osteophytic overgrowth, or bony volume expansion in the osteosclerotic phase (see later) can all impinge on neural elements.¹⁷⁹ The spinal cord’s vascular supply can likewise be disrupted by bone compression of afferent arteries, leading to neural ischemia. In addition, Paget disease causes a reactive vasodilation near diseased areas. This may lead to shunting of blood and ischemia of the deprived areas. In the spine, increased blood flow around pagetic lesions may result in a diversion of blood destined for the cord, causing the so-called arterial steal phenomenon and leading to neurologic signs. In summary, spinal Paget disease can cause not only bone pain and arthritis or pathologic fractures but also, through its effect on nerves, headaches, hearing or vision loss, cerebellar deficits, and even fecal and urinary incontinence.

FIGURE 87–6 Spinal involvement in Paget disease. The vertebral body is squared and enlarged.

A hallmark of Paget disease is skeletal deformity, which may be manifest as an increase in bone size or an abnormality in their shape. Bone is resorbed and replaced rapidly in Paget disease, and the replacement bone is necessarily less organized and weaker. In weight-bearing bones, this can cause skeletal deformities.¹⁸⁰ Although this problem is more common in the femur and tibia, it can occur in the spine, leading to significant kyphotic changes.

Paget disease can also cause high-output cardiac failure. This rare occurrence is not due to increased blood flow within the Pagetic bone but rather to reactive vasodilatation of the tissue adjacent to the involved bone. This increased vascular flow explains the skin warmth felt over the involved bone and, as discussed earlier, may cause ischemia in regions where the blood normally flows.

The most serious clinical complication of Paget disease heralded by the acute onset of pain or sharp increase in the intensity of chronic pain is osteosarcoma or other types of sarcoma. Although the incidence of osteosarcoma is less than 1% of patients with Paget disease, it is 1000 times higher than in the general population for this age group.¹⁸¹ Moreover, the tumors that do form are particularly aggressive. Fortunately, sarcomatous degeneration is especially infrequent in spinal Paget disease. An unusual form of tumorous degeneration in Paget disease is the giant cell tumor. The lesion is frequently multifocal and has a unique association with individuals from Avellino, Italy.¹⁸² The tumor frequently involves the spine and leads to paraplegia unless treated. It responds to dexamethasone therapy, which can be augmented by selective radiation.

Other clinical manifestations of Paget disease may be related to the phase of the patient’s disease. During the early osteolytic phase, for example, the patient may suffer the consequences of bone loss such as a pathologic fracture, whereas in the late sclerotic phase, arthritic complaints predominate. Furthermore, Paget disease may advance geographically within a bone or may progress from a monostotic disease to one involving many bones. A mixed picture, therefore, may be observed with lysis in some areas and sclerosis in others.

Diagnosis

Treatment