Renal osteodystrophy

Progress in Pathology Renal Osteodystrophy STEVEN L. TEITELBAUM,MD Since the time of Rudolf Virchow, pathologists have been central to the diagnosis of skeletal diseases. Indeed, it is Virchow's description of the morbid anatomy of various infections and generalized disorders of bone that forms the fotmdation of physical anthropology. 1 In this century, however, most pathologists have focused largely on neoplastic and infectious bone diseases, while the diagnosis of generalized or metabolic disorders o f the skeleton has largely become the purview of the physician. The reasons for pathologists' loss of interest in the diagnosis of generalized bone diseases are unclear, but it is unfortunate; because, as compared with bone tumors, this fami!y of diseases is far more common and has much greater social impact. Furthermore, the bone biopsy an'd its histologic evaluation are pivotal in the diagnosis of metabolic bone diseases, thereby inviting the pathologist to play an important role in their management. In this review, I have focused on renal osteodystrophy as a paradigm of a metabolic bone disease. I have chosen uremic bone disease because virtually ever)' physiologic or anatomic abnormality of the skeleton may be encountered in patients with renal failure. Therefore, appreciation of the skeletal manifestations o f uremia requires a general u n d e r standing of the physiologic and pathologic manifestations of mineral metabolism.

uremia the balance is generally in favor of resorption, leading to mobilization of skeletal mineral and, therefore, a net rise in blood calcium levels. 5-s Parathyroid hormone also increases blood calcium levels by enhancing the renal tubular reabsorption of calcium and by promoting phosphaturia. 9 The latter event is among the most sensitive indicators of parathyroid h o r m o n e administration and leads to elevation of blood calcium levels because of the reciprocal relation between circulating calcium and phosphorus. T h e other primary effect of parathyroid hormone in the renal tubule involves the metabolism of vitamin D. Some vitamin D is acquired through dietary sources, but the primary source is ultraviolet irradiation of its skin-residing precursor, 7-dehydrocholesterol. 10,11 Once in the circulation, vitamin D is transported to the liver, where it undergoes hydroxylation at carbon 25 to form 25-hydroxyvitamin D, 12,13 which normally circulates in nanogram concentrations. Indeed, measurement of 25-hydroxyvitamin D is the most reliable method for determining the level of vitamin D stores within the body. A small fraction of 25-hydroxyvitamin D (approximately 1/1000 o f circulating levels) is transp o r t e d to the kidney, where it is h y d r o x y l a t e d at carbon 1, primarily under the influence of parathyroid hormone, to form 1,25-dihydroxyvitamin D, which is the most biologically potent form of the vitamin) 4 1,25-Dihydroxyvitamin D raises blood calcium levels by enhancing the absorption of calcium from the intestine 15 and by promoting bone resorption, 16 particularly in association with parathyroid hormone.17

MINERAL HOMEOSTASIS The skeleton is influenced by an infinite array of circulating factors, but abnormalities of parathyroid hormone and vitamin D metabolism probably have the greatest impact on the development of uremic bone disease. Parathyroid hormone is secreted by the parathyroid glands, largely, if not exclusively, under the influence of the circulating levels of ionized calcium. 2 While this hormone probably has a more generalized effect, its major known targets are kidney and bone. In bone, parathyroid hormone functions as an activator of both osteoclasts 3 and osteoblasts 4 within the context of the remodeling process (vide infra). Although both types of bone,cells are stimulated by parathyroid h o r m o n e , in the absence o f

STRUCTURE OF BONE Bone Cells

Received from the Department of Pathology and Laboratory Medicine, The Jewish Hospitalof St. Louis, Washington University School of Medicine, 216 South KingshighwayBoulevard,St. Louis, MO 63178. Accepted for publication November 29, 1983. Supported in part by a gift from the Jewish Hospital of St. Louis Auxiliary. Address correspondence and reprint requests to Dr. Teitelbaum.

T h e e n d o g e n o u s cells of bone include osteoblasts, which synthesize bone, osteoclasts, which resorb it, and osteocytes, which are osteoblasts that have been incorporated into the matrix. Osteoblasts are derived from fibroblast-like, marrow-residing precursorslS. 19 and generally assume a morphology that reflects their bone-synthesizing activity. 20,~1 When actively producing bone, these cells always line a seam o f osteoid (unmineralized bone matrix). Under these circumstances, osteoblasts are cuboidal to columnar and have prominent Golgi zones and endoplasmic reticula (fig. 1). As the rate of bone formation slows, osteoblasts become progressively attenuated. T h e s e fusiform cells cover the majority of bone surfaces and hence are often r e f e r r e d to as "bone lining cells" (fig. 2).

306

RENAL OSTEODYSTROPHY(Teitelbaum)

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FIGURE t (top left). Cuboidal, seemingly active osteoblasts lining a thick osteoicl seam (O). These cells, which are typical of cells that are rapidly synthesizing bone, possess prominent Golgi zones (arrow). (UnclecaIcified, Golclner stain, x 250.) FIGURE 2 (top right). Fusiform, seemingly inactive osteoblasts lining a thin osteoid seam (arrow). These cells ore generally associated with bone surfaces that are undergoing neither matrix synthesis nor mineralization. (Unclecalcitiecl, Golclner stain. x 250.) FIGURE 3 (left). Numerous osteoclasts in a cleep Howship's lacuna. (Undecalcified, Goldner stain, x 250.)

As the osteoblasts produce bone, some of them are incorporated into the matrix as osteocytes. These cells are housed in lacunae, the size of which reflects the activity of their parental osteoblasts. 20 In other words, osteoblasts tliat are actively synthesizing bone are large and hence, when incorporated into matrix, must be contained in relatively large lacunae, whereas the smaller, relatively inactive cells require less space. These differences in lacunar size have been. interpreted as reflecting "osteocytic osteolysis. ''22-25 There is no evidence, however, that osteocytes have the capacity to resorb bone. 26 Alternatively, it is likely that osteocytes play a role in mineral homeostasis. The most reasonable hypothesis is based on the fact that these cells are in physical contact with each other and with overlying osteoblasts and are hence likely to form an anatomic syncytium.27 The syncytium is believed by some to serve as a cel-

307

lular barrier that isolates the bone fluid compartment, with its abundance of calcium, from the general extracellular space. 28,29 Osteoclasts are the large, muhinucleated cells that are responsible for bone degradation (fig. 3). It is now established that the ontogeny of these cells differs from that o f osteoblasts, and, in fact, the weight of evidence points to a monocyte/macrophage precursor of osteoclasts.30-33 Althongh the precise mechanisms by which osteoclasts degrade bone are poorly understood, the anatomy of the resorptive process is well described. 34 Osteoclasts attach to bone via an actin-rich, organellefree "clear zone," which, in the resorbing cell, surrounds a ruffled border. Tiffs complex enfolding of cell membrane (ruffled border), which can be appreciated only by electron microscopy, is the sine qua non of the active osteoclast and, in fact, is the only

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feature that distinguishes it with certainty from other macrophage-derived giant cells (fig. 4).

use of tetracylines as anatomic markers of mineral deposition is central to the histomorphometric analysis of bone.

O r g a n i c Phase

ANATOMIC PHYSIOLOGY OF BONE

More than 90 per cent of the organic phase of bone is collagen, 35 which is also the component most easily studied morphologically. On polarizing microscopy, bone collagen in persons older than 4 years of age exhibits a lamellar pattern characterized by parallel units of individual collagen fibers 36 (fig. 5). In contrast, fetal bone collagen has a r a n d o m or "woven" arrangement (fig. 6). Woven collagen is also formed in adult bone in states of accelerated bone turnover, such as fracture repair, Paget's disease, or renal osteodystrophy. Consequently, the presence of woven bone in the adult skeleton is always indicative of a pathologic process. T h e noncollagenous organic c o m p o n e n t s o f bone are n o t easily distinguished morphologically, but t h e y ! m a y be i m p o r t a n t to skeletal structure. Glycosaminoglycans37 and phospholipids3S, 39 are believed to play a role in the mineralization process. A group of recently described noncollagenous proteins are of particular interest as they may be crucial to less understood skeletal activities, such as binding of mineral to collagen and recruitment of precursor cells to bone.40-45 Mineral Phase

Bone formation occurs by the synthesis and then mineralization of organic matrix. Ultimately, mineral deposition parallels the distribution of collagen fibers, and, in fact, loss of the organic matrix of bone leaves a mineralized model of collagen fibers. 46 An understanding of the process of skeletal mineralization is essential to the histomorphometric analysis of bone because the techniques for the microscopic measurement of the kinetics of bone formation depend on determination of the rate of mineralization. Bone mineral exists in at least two phases, the physical chemistry of which is poorly understood. 4750 It is known, however, that the mineral is deposited in an "immature" form, which after a short period u n d e r g o e s t r a n s f o r m a t i o n into a m o r e " m a t u r e " phase. T h e importance to the bone pathologist of this phase transformation is related to the capacity of immature bone mineral to complex tetracyclines. Tetracyclines are autofluorescent antibiotics 51 that bind stoichiometrically to newly deposited bone mineral. 49-5-9 Consequently, when non-decalcified histologic sections of bone are viewed in a fluorescence microscope, mineral that is newly deposited at the time of tetracycline administration is m a r k e d by a bright fluorescent line. In lamellar bone, this immature mineral is deposited at the interface of osteoid and mineralized bone, a site known as the calcification front ~3 (fig. 7). With time, this mineral is transformed into a phase that constitutes the great majority of the skeleton and is incapable of binding tetracycline. T h e 308

The consequences of bone cell function that are apparent at the histologic or gross level include 1) growth, 2) modeling, 3) remodeling, and 4) repair (fracture healing),Sl all of which may be deranged in uremia. 54-56 Growth and modeling occur only prior to growth plate (physis) closure and reflect increasing skeletal mass and the movement of bone through space, respectively. Growth occurs by either endochondral or i n t r a m e m b r a n o u s ossification. Endochondral growth involves expansion of the cartilaginous physis and its parallel replacement by bone. Int r a m e m b r a n o u s bone formation entails direct production of bone by osteoblasts that do not pass through a cartilaginous stage. 57 The development o f a fetal bone into its similarly shaped, yet many times larger, adult counterpart requires not only increases i n mass but also sculpting or movement through space. Derangements in this process o f modeling in face of persistent growth result in a skeleton o f n o r m a l height but d e r a n g e d shape. Many o f the developmental skeletal dysplasias are disorders of modeling. Clearly, skeletal enlargement and sculpting involve formation of bone in some areas and its removal ih others; hence, both growth and modeling depend on an anatomic dissociation of the activities of osteoblasts and osteoclasts. In contrast, remodeling, a process that occurs throughout life and is intimately associated with mineral homeostasis, is characterized by a coupling of osteoclast and osteoblast recruitment. 57 Remodeling is initiated by the appearance of osteoclasts, which resorb a packet of bone, forming a Howship's lacuna in trabecular bone or a cutting cone in the cortex. After excavation of a cavity approximately 50 p.m deep, 5s the osteoclasts disappear and are eventually replaced by osteoblasts, which deposit new bone within the resorption bay. The tethering of osteoclasts and osteoblasts in remodeling is anatomic, not kinetic. Hence, the speed at which osteoblasts deposit bone need not parallel the previous rate of resorption. In fact, with age, more bone is resorbed at remodeling sites than is subsequently deposited. 59 It is this kinetic dissociation of osteoclastic and osteoblastic activity that is responsible for the bone loss that univerisally attends aging. Furthermore, because of the anatomic coupling of remodeling osteoclasts and osteoblasts, most agents that affect the size of one population of cells alter the other in a similar fashion. Parathyroid hormone is a case in point. This hormone, which is a potent activator of the remodeling process, increases the numbers of both osteoclasts 3 and osteoblasts, 4 whereas calcitonin, which inhibits remodeling, has the opposite effect.6~ This tethering of bone-resorbing and -forming cells leads to difficulty in the treatment of osteopenic diseases. For ex-

RENAL OSTEODYSTROPHY [ T e i t e l b a u m ]

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Volume 15, No. 4 (April 1984]

FIGURE 5 (top). Lamellar bone collagen viewed by polarizing microscopy. (Decalcified hematoxyiin-eosin stain, x 160.) FIGURE 6 [bottom]. Woven bone collagen viewed by polarizing microscopy. (Decalcified, hematoxylin-eosln stain, x 160.)

310

RENAL OSTEODYSTROPHY{Teitelbaum]

FIGURE 7. Bone taken from a patient shortly [three days) after administration of a course of tetracycline. The fluorescent band represents deposition of the antibiotic at the calcification front, which is located at the interface of osteoid [arrow) and mineralized bone. [Undecalcified, unstained, x 100.)

consequently, identification o f patients with excess osteoid (hyperosteoidosis). T h e importance of identifying patients with excess osteoid is related to the histologic heterogeneity of the osteopenic skeleton. 63 Osteopenia is a generic term indicating insufficient bone mass as diagnosed by nonhistologic means, such as radiography. Use o f the term also implies little insight into the pathogenesis of the particular skeleton under study. Unlike osteopenia, osteoporosis and osteomalacia are histologically defined entities. Osteoporosis refers to a decreased mass of normally mineralized bone. The osteoporotic biopsy specimen, therefore, consists o f a thin cortex, small trabeculae, and a normal ratio of mineralized bone to osteoid. Osteomalacia, on the other hand, is defined as excess osteoid due to a decreased rate of mineralization. Although osteomalacic patients are often osteopenic, they may have normal or even increased bone mass. However, histologic demonstration o f excess amounts of osteoid (hyperosteoidosis) is essential to the diagnosis of this disorder (fig. 8). While hyperosteoidosis is a fimdamental component of the osteomalacic state, not all patients with excess osteoid have osteomalacia. This is due to the fact that the quantity of osteoid reflects two simultaneously occurring kinetic events: 1) the rate of osteoid synthesis and 2) the rapidity of mineralization. Hence, excess osteoid may accumulate when the rate of osteoid synthesis is enhanced or when mineralization is slow (osteomalacia). Distinction between these

ample, if bone loss is due to decreased formation, administration of an agent capable of enhancing matrix synthesis usually also promotes resorption. HISTOLOGIC METHODS FOR DIAGNOSIS

Renal osteodystrophy is a metabolic bone disease; because the common element of such diseases is diffuse skeletal involvement, the histologic features of bone at any site may be extrapolated to the skeleton at large. This realization makes the r a n d o m ("blind") biopsy central to the study of these disorders. T h e importance of bone biopsy in the management of metabolic bone diseases reflects two major technical achievements. The first is the development of relatively atraumatic methods for obtaining wellpreserved samples of bone. T h e biopsy specimens are obtained from the iliac crest with a variety of specifically designed trocars. 6] We perform these biopsies as an outpatient procedure, using local anesthesia. The fact that virtually all of our patients undergo repeat biopsy is testimony to the relatively atraumatic nature of the procedure, The second major advance in bone histology is the development of techniques by which non-decalcified sections may be prepared. 62 These sections are essential to the bone pathologist because, unlike decalcified material, they permit easy distinction of mineralized from nonmineralized bone matrix and, 3tt

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Q

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FIGURE 8. Top, nondecalcified section of normal trabecular bone. Boflon~ non-decalcified section of osteoporotic trabecular bone. Bone mass is diminished, but osteoid is not increased. Facing page, non-decalcified section of trabecular bone from an osteopenio patient with hyperosteoidosis. Bone mass is diminished, but the ratio of osteoid [arrow] to mineralized bone is increased. [Undecalcified, Goldner stain, x 160.]

312

RENALOSTEODYSTROPHY(Teitelbaum]

FIGURE 8 [continued]. Legend appears on facing page.

two kinetic events is more than academic, particularly in such states as renal osteodystrophy, in which the nature of the hyperosteoidosis dictates therapy (vide infra). T h e r e are standard (static) histologic features that, in a general way, suggest the mechanism of osteoid accumulation. For example, an excess of cuboidal, seemingly active osteoblasts is indicative of accelerated bone formation. Unfortunately, however, these nonkinetic features may be misleading64 and are o f little use in determining the absolute rate of osteoid synthesis or mineralization in a particular patient. In contrast, tetracyclines, because of their fluorescent properties a n d their capacity to chelate newly deposited bone mineral stoichiometrically, allow distinction of the various forms of hyperosteoidosis. 6~ I f the antibiotic is administered shortly (within three days) before biopsy, the proportion of osteoblasts taking part in the mineralization process can be determined. This determination is ma'de by measuring the fraction of the osteoid-mineralized bone interface (calcification front) that exhibits a fluorescent tetracycline label (fig. 7). In states of accelerated osteoid synthesis in which mineral is deposited at normal or increased rates, most of the calcification front will fluoresce owing tetracycline deposition. In osteomalacia, however, osteoblasts fail to deposit mineral in sufficient quantities to bind tetracycline, and

hence most o f the calcification f r o n t will not flnoresce. T h e absence o f tetracycline fluorescence is an important criterion of osteomalacia. However, it is not a kinetic parameter and therefore does not allow direct m e a s u r e m e n t o f the rate of mineralization. This information may be obtained, however, by administration o f i n t e r m i t t e n t courses o f the antibiotic. 66 In our unit, we deliver two three-day courses of tetracycline separated by a 14-day interval. This a p p r o a c h leads to the a p p e a r a n c e o f n u m e r o u s "double labels." The deeper label represents the first course of tetracycline, and that at the calcification front, the second (fig. 9). Use of a linear micrometer permits easy determination of the mean distance between these parallel double labels. This factor, when divided by the interdose duration, yields the celhdar rate of mineralization, or the rate at which the averag e osteoblast mineralizes osteoid in an appositional fashion (i.e., perpendicular to the osteoid surface). In osteomalacic states, osteoid accumulates owing to retarded mineralization, and the mean distance between tetracycline labels is therefore generally subnormal. In contrast, when hyperosteoidosis is due to enhanced organic matrix synthesis, the cellular rate of mineralization is at least normal. This distinction is often best expressed in terms of the mineralization lag time, 67 which is derived by dividing the average width of osteoid seams by the product of the cellular

313

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FIGURE 9 [fop). Double fluorescent tetracycline labels, reflecting two courses of the antibiotic separated by a 14-day interval. [Nondecalcified, unstained, x 160.] FIGURE t0 [bottom]. Wide and irregular fluorescent tetracycline labels in bone from a patient with osteomalacic renal osteodystrophyo These wide labels reflect an excess of "immature" bone mineral. [Undecalcified, unstained, x160.]

314

RENAL OSTEODYSTROPHY(Teitelbaurn]

rate of mineralization and the fraction of osteoid seams that assume a fluorescent label. This variable reflects the interval between organic matrix deposition and mineralization. A prolonged mineralization lag time invariably means that osteomalacia is present. This discussion has addressed quantification of the rate o f bone mineral deposition. Another form of defective mineralization, however, involves mineral maturation. As stated previously, "immature" mineral, u n d e r normal circumstances, undergoes transformation into a " m a t u r e , " nontetracycline binding phase. In numerous disorders, including particular forms of renal osteodystrophy, the rate of mineral maturation is retarded. 6s,60 Hence, excessive immature bone mineral exists at the calcification front, leading to wide and irregular tetracycline labels 7~ (fig. 10). Diffuse labeling is also encountered in association with woven bone. 71 This phenomenon indicates that such bone contains an abundance of immature mineral, which probably contributes to the structural inferiority o f the tissue c o m p a r e d with its lamellar counterpar(. PATHOGENESIS AND PATHOLOGIC FEATURESOF RENAL OSTEODYSTROPHY

All of the biochemical and morphologic abnormalities that attend kidney dysfunction are seen in renal osteodystrophy. While skeletal abnormalities a p p e a r early in renal failure, 72 the most dramatic changes occur in patients with end-stage kidney disease who are maintained by lifesupport systems, such as hemodialysis. Therefore, advanced uremic bone disease is, in a sense, an iatrogenic disorder that in most instances can be successfully treated (vide infra). 9 The morphologic manifestations of renal osteodystrophy include combinations of hyperparathyroid bone disease and osteomalacia in a setting of reduced, normal, or increased bone mass. T h e specific manifestations of the disorder are greatly influenced by geography, with hyperparathyroid osteodystrophy predominating in the United States 73 and osteomalacia in Great Britain. 74 Parathyroid hormone excess occurs earl), in renal failure 75 and is virtually ubiquitous in end-stage d i s ease. 76 In fact, hemodialyzed patients have the highest circulating levels of immunoreactive parathyroid hormone, which in our center average 30 to 60 times the normal level. 77 On the other hand, most immunoassays recognize the carboxyl oi" nonbiologically active portion of the parathyroid hormone molecule. Consequently, much o f the hormone measured in renal failure, a state characterized by delayed processing o f parathyroid h o r m o n e fragments, represents nonfunctional material. 7s In an)' event, appreciation o f the genesis o f h y p e r p a r a t h y r o i d i s m in uremia is pivotal to understanding uremic bone disease in this country and has led to dramatic advances in the prevention and cure of renal oste0dystrophy. While man)' factors undoubtedly contribute to 3t5

the development of uremic hyperparathyroidism, tile two most important are probably abnormalities of phosphorus75, 79-81 and vitamin D sl,s2 metabolism. The initial event in uremic hyperparathyroidism appears to be progressive failure of the renal tubule to excrete phosphorus, leading to retention of the anion in the circulation. T h e hyperphosphatemia causes a reciprocal reduction in blood calcium levels, which in turn promotes parathyroid hormone secretion. This sequence o f events leads to normalization of blood calcium and phosphorus levels in early and moderate renal failure, but at the cost of increased levels of circulating parathyroid hormone. Normalization of phosphorus and calcium levels is accomplished by p a r a t h y r o i d h o r m o n e - i n d u c e d phosphaturia, enhanced renal tubular reabsorption of calcium, synthesis of 1,25-dihydroxyvitamin D, and mobilization of calcium from bone. With advancing renal insufficiency, the tubule loses its capacity to respond to parathyroid hormone, leading to profound hyperphosphatemia, persistent hypocalcemia, and severe hyperparathyroidism. At this stage, the situation is compounded by progressive failure of the kidney to synthesize 1,25-dihydroxyvitamin D, resulting in diminished intestinal absorption o f calcium, which contributes to the attendant hypocalcemia and hyperparathyroidism. T h e skeletal manifestations of hyperparathyroidism are included in the group of changes kno~'n as osteitis fibrosa. Osteitis fibrosa is a histologic entity that invariably reflects accelerated bone turnover. While these changes are common in all forms of hyperparathyroidism and are generally most dramatic in end-stage renal disease, they also occur in other states of accelerated remodeling, such as hyperthyroidism and Paget's disease. Because osteitis fibrosa is a remodeling disorder, increased numbers of both osteoclasts and osteoblasts are encountered (fig. 11). The resorptive cells are often found in deep Howship's lacunae, in numerous cortical cutting cones, and at the subperiosteal surface. Subperiosteal bone resorption normally occurs in the growing skeleton because of the demands of modeling. 57 In the adult, however, osteoclastic activity at the subperiosteal surface is distinctly abnormal and always represents accelerated bone turnover. Osteoid is generally excessive in patients with end-stage uremia and is most often a manifestation of increased coverage o f trabecular bone surfaces rather than of enhanced seam thickness. 77 The quantity of osteoid and the rate of its synthesis and mineralization, as measured by tetracycline labeling, typically parallel the level of circulating parathyroid hormone in u r e m i a 77 (fig. 12). Because p a r a t h y r o i d hormone levels generally increase with progressive renal failure, the predominant mechanism by which most patients with end-stage kidney disease accumulate osteoid is acclerated organic matrix synthesis. 76 This rapid deposition of collagen is also manifested by an abundance of both couboidal osteoblasts and woven bone.

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FIGURE 11, Osteitisfibrosa with excess osteoid {O] and increased numbers of o~teoblasts and osteoclasts (a deep Howship's lacuna is visible]. The characteristic feature is peritrabecular marrow fibrosis [F]. [Undecalcified, Goldner stain, x 100.}

The diagnostic hallmark of osteitis fibrosa, however, is a particular form of marrow fibrosis. Fibrous tissue deposition under these circumstances probably represents the actMty of stimulated osteoblast pre-

cursors and ahvays occurs in juxtaposition to the bone surface (fig. 11). In contrast, the fibrous tissue of idiopathic myelofibrosis is r a n d o m l y distributed throughout the marrow space. Peritrabecular fibrosis is the hallmark of osteitis fibrosa, and its presence, even in small samples of bone, establishes tile disagnosis of this lesion. Osteomalacia is generally the m o r e crippling form of uremic bone disease, and its pathogenesis is only beginning to be understood. For some time, abnormalities of vitamin D metabolism were considered central to the d e v e l o p m e n t of renal osteomalacia. The genesis of this hypothesis is based on the fact that all patients with end-stage renal disease have abnormal vitamin D, particularly 1,25-dihydroxyvitamin D, metabolism. Specifically, advanced renal failure is always associated with loss of the capacity of the kidney to synthesize 1,25-dihydroxyvitamin D; thus, circulating levels of 1,25-dihydroxyvitamin D in patients u n d e r g o i n g hemodialysis are either extremely low or undetectable.83, 84 On the other hand, 9it has not been shown that vitamin D directly stimnlates bone mineralization; in fact, any form of vitamin D cures renal osteitis fibrosa more effectively than osteomalacia (vide infra). Recently, two pathogenetic mechanisms have been presented as probable causes of. uremic osteomalacia. T h e first is absolute or relative hypoparathyroidism. We observed the development of severe

FIGURE 12. Fluorescence micrograph of bone from a uremic patient with severe hyperparathyroidism. Tetracycline uptake is markedly increased, reflecting very rapid bone mineralization.The area encompassed by tetracycline fluorescence represents the quantity of bone mineralized in a 14-day period. [1Jndecalcified, unstained, x 100.]

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RENALOSTEODYSTROPHY(Teitelbaum)

and intractable osteomalacia in uremic patients who had undergone parathyroidectomy. 76 O f even more concern, Weinstein s5 r e p o r t e d the d e v e l o p m e n t of osteomalacia in patients with end-stage kidney function who had u n d e r g o n e partial parathyroidectomy. s5 These observations have led many to consider a certain amount of parathyroid !~ormone essential for optimal skeletal homeostasis in uremia and have raised concern regarding the use of parathyroidectomy to treat uremic h y p e r p a r a t h y r o i d i s m . T h e amount of functioning parathyroid tissue necessary for optimal skeletal function is currently unknown. While hypoparathyroidism may contribute to the development of uremic osteomalacia, the major culprit appears to be aluminum. This conclusion is derived from the work of Ellis et al., s6 who showed that systemic administration of aluminum to rats leads to severe osteomalacia. Ott and co-workers s7 subsequently demonstrated accumulation of the cation in the bone of uremic patients with'6steomalacia by both biochemical and histologic techniques. Furthermore, aluminum weferentially accumulates in parathyroid tissue s8 and !suppresses parathyroid hormone secretion in vitro, s~ These observations suggest that, in addition to a direct effect on bone, aluminum may cause osteomalaciaby inducing relative hypoparathyroidism. The major source of the aluminum transferred to uremic bone has been water used for dialysis, oo This discovery has clarified the striking geographic distribution of the lesion in the United States. On the other hand, aluminum-induced osteomalacia also develops in patients who are dialyzed only against aluminumfree water. It is most likely that under these circumstances the cation is absorbed from the intestine and reflects the abundant use of aluminum-rich, phosphate-binding gels in uremic patients. 01 Uremic osteomalacia is characterized by an abundance of osteoid. Unlike osteitis fibrosa, however, osteomalacic osteoid seams are generally covered by fusiform, "bone lining" cells. Moreover, the interface between osteoid and mineralized bone tends to be smooth in osteomalacia, whereas that of osteitis fibrosa is usually serrated (fig. 13). This difference undoubtedly reflects the low and increased rates of remodeling in osteomalacia and osteitis fibrosa, respectively. Osteoclasts are relatiely sparse in severe uremic osteomalacia, and marrow fibrosis is typically not present. T h e paucity of bone-resorbing cells reflects, m part, the comparatively low levels of parathyroid hormone circulating in patients with this lesion. 76 In addition, however, osteoid is resistant to osteoclastic resorption. 02 Observations made in our laboratory indicate that this resistance reflects the inability of osteoclast precursors to attach to unmineralized bone matrix 03 and to differentiate into osteoclasts. 04 The histologic diagnosis of osteomalacia rests on tetracycline labeling. T h e characteristic alteration in osteomalacic patients is the failure of most of the calcification front to assume a tetracycline label (fig. 14). 317

At the few locations where fluoresence is observed, the label is generally wide and irregular, consistent with a delay in the rate of mineral maturation. On the other hand, the distance between the rare double labels that are present may be normal in uremic osteomalacia. 76. These accumulated tetracycline-based observations indicate that the osteomalacia in renal insufficiency often involves failure to recruit sufficient numbers of bone-mineralizing osteoblasts. Alternatively the bone-forming cells that are successfully recruited may function normally. Because of the role of aluminum in the pathogenesis of osteomalacia, it is particularly important to determine w h e t h e r uremic bone biopsy specimens contain aluminum. Fortunately, the cation is easily demonstrated histologically s7 (fig. 15). When present in bone, aluminum preferentially accumulates at the calcification front. It appears to compete with the normal mineralization process, as evidenced by failure to assume a tetracycline label at that site. Uremic Bone Mass

As stated previously, uremic patients may have decreased, normal, or increased quantities of bone. Because renal failure generally leads to osteoid accumulation, most osteopenic patients with uremia have osteomalacia and/or osteitis fibrosa. In contrast, osteoporosis is a rare form of renal bone disease. Osteosclerosis means increased bone mass per unit marrow space and may be the most common form of renal osteodystrophy. 95 Development of the lesion generally parallels that of hyperparathyroidism and the duration of chronic renal failure 72 and is most dramatically manifested radiographically as the "rugger-jersey" spine (fig. 16). T h e increased bone mass of uremia is exclusively a trabecular phenomenon. Thick trabeculae are typically e n c o u n t e r e d in association with marked increases in cortical bone porosity. T h e concomitant gain of cancellous bone and diminution of cortical mass lead to loss o f histologic distinction between cortex and trabeculae (fig. 17). It also accounts for the fact that uremic osteosclerosis occurs predominantly in the axial skeleton, which is largely trabecular, while appendicular bone, which is mostly cortical, may simultaneously become osteopenic. Because the d e v e l o p m e n t of uremic osteosclerosis generally occurs in patients with advanced hyperparathyroidism, their skeletons usually contain severe osteitis fibrosa. Osteoid is abundant, despite the increase in mineralized bone mass, and some patients may have osteosclerosis in association with osteomalacia. The genesis of osteosclerotic osteomalacia is unclear but may be related to the known inability of osteoclasts to d e g r a d e osteoid, 9z thereby insulating the underlying mineralized bone from resorption. Despite the occasional patient with osteosclerotic osteomalacia, the predominant cellular event leading to uremic osfeosclerosis is clearly enhanced osteoblastic activity. 76

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Volume 15, No. 4 [April 1984]

FIGURE 13 (top]. Severe uremic osteomalacia (compare with fig. tl). [Undecalcified, Goldner stain, x 100.) FIGURE 14 [bottom]. Fluorescence micrograph of bone from a uremic patient with osteomalacia. Most of the calcification front fails to assume a fluorescent tetracycline label. Where present, only single fluorescent labels are seen. The arrow designates osteoid. [Undecalcified, unstained, x160.)

318

RENAL OSTEODYSTROPHY (Teitelbaum]

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F I G U R E ~fi. T h e d a r k line at w h a t a p p e a r s to b e t h e p e r i p h e r y of this t r a b e c u l u m is histologically identifiable a l u m i n u m in a patient with u r e m i c o s t e o m a l a c i a , T h e cation is actually p r e s e n t at the calcification front, but osteoid is not well visualized with this stain. [Undecalcified, e T u m i n o n stain., x'100.)

CLINICOPATHOLOGIC

CORRELATIONS

T h e development o f histologic techniques for the examination of the uremic skeleton has been paralleled by the development of an array of sophisticated biochemical and radiologic tests9 It is, therefore, appropriate to ask which, if any, of these noninvasive tests can predict the histologic features of uremic bone and in which patients biopsies must be done. We and others have examined this issue and have found that circulating immunoreactive parathyroid hormone and alkaline phosphatase activity,30,96 with the characteristic radiographic changes,39,97 are reasonably predictive of osteitis fibrosa. On the other hand, it is generally possible to diagnose osteomalacia by noninvasive techniques 3~ only in the rare patient (in the United States) with pseudofractures (Looser's zones). These observations suggest that the bone biopsy is most important in uremic patients who do not have evidence o f severe hyperparathyroidism yet have clinically apparent bone disease9 Moreover, we have found the bone biopsy essential for evaluating adequacy of treatment of renal osteodystrophy.

PATHOLOGIC MANIFESTATIONS OF TREATMENT

Renal osteodystrophy is probably the most successfully treated metabolic bone disease9 This success reflects the insight gained into both the pathophysiologic features of this disorder and the mechanisms

FIGURE t6. Vertebral column of a uremic patient with osteosclerosis showing alternating bands of increased a n d normal radiodensity.

319

HUMAN PATHOLOGY

Volume 15, No. 4 (April 1984)

FIGURE t7. Uremic osteosclerosis. Both trabecular bone mass and cortical porosity are increased, leading to loss of distinction between cortex and trabeculum. P, periosteum. (Undecaleified, modified Masson stain, x 30.)

flecting.a biochemically documented shift toward mature bone mineral. 7~ In fact, improvement of the biochemical abnormalities associated with uremic bone may precede histologic changes, l~ A h h o u g h less c o m m o n than osteitis fibrosa in this country, renal osteomalacia is currently responsible for most clinically significant uremic bone disease. Unfortunately, with the possible exception of 24,25-dihydroxyvitamin D, osteomalacia generally fails to respond to vitamin D treatment. 1~ This observation underscores the lack of evidence that abnormalities of vitamin D metabolism contribute to the development of uremic osteomalacia. On the other hand, the realization that aluminum intoxication is often responsible for this lesion has led to the use of drugs that are potentially capable of extracting the cation f r o m bone. Preliminary studies with these compounds are promising 1~ and have, in man)' instances, demonstrated removal of all histologically evident skeletal aluminum. Such treatment is also associated with the conversion of uremic osteomalacia to osteitis fibrosa. T h e genesis of this change is yet to be determined but may involve enhanced secretion of parathyroid hormone due to removal of aluminum from tl~e parathyroid glands and/or increased responsivity o f aluminum-free uremic bone to this hormone.

o f normal mineral homeostasis. Clearly, osteitis fibrosa is the renal b o n e disease most a m e n a b l e to treatment. The realization that parathyroid hormone secretion is controlled by circulating calcium levels has led to the management o f uremic hyperparathyroidism by high calcium supplementation via dietary and dialytic means, s~ In addition, prevention of excessive phosphorus absorption by dietary restriction and the use of phosphorus-binding gels has also had a great impact on the treatment of uremic hyperparathyroidism. 9s Perhaps the major recent advance in the management of this complication is the synthesis of newly discovered metabolites of vitamin D. These compounds increase calcium balance by enhancing intestinal absorption of the cation and therefore suppress parathyroid hormone secretion. 99,I00 The reversal of uremic osteitis fibrosa with 25hydroxyvitamin D or 1,25-dihydroxyvitamin D is dramatic and generally occurs after three to s~x months of therapy. Marrow fibrosis and woven bone diminish or disappear, the numbers of osteoclasts and osteoblasts are reduced, and the quantity o f osteoid decreases. Occasionally, osteoid seams are "buried" in mineralized trabeculae, indicating the preferential mineralization of bone matrix deposited after initiation of vitamin D treatment. 99 Tetracycline labels in such patients also become narrow and regular, re320

RENAL OSTEODYSTROPHY(Teitelbaurn]

REFERENCES 1. Virchow R: Cellular Pathology (translated front the Second German Edition by Chance F). New York, Dover Publications, 1971, p 471 2. Sherwood LM, Mayer GP, Ramberg CF, et al: Regulation of parathyroid hormone secretion: proportional control b)" calcium, lack of effect o f phosphate. E n d o c r i n o l o g y 83:1043, 1968 3. King GJ, Hohrop ME, Raisz LG: The relation of uhrastructural changes in osteoclasts to resorption in bone cultures stimulated with parathyroid hormone. Metabol Bone Dis 1:67, 1978 4. Melsen F, Mosekilde L: Trabecular bone mineralization lag time determined by tetracycline double-labeling in normal and certain pathological conditions. Acta Pathol Microbiol Stand [A] 88:83, 1980 5. Tougaard L, Hau C, Rodbro P, et al: Bone mineralization and bone mineral content in p r i m a r y hyperparathyroidism. Acta Endocrinol 84:314, 1977 6. Forland *I, Strandjord NM, Paloyan E, et al: Bone density studies in primary h)'perparathyroidism. Arch Intern Med 122:236, 1968 "~. 7. KnopJ, Montz R, Schneider C, et al: Bone calcium exchange in primaiy hyperparathyroidism as measure d by 47calcium kinetics. Metabolism 29:819, 1980 8. Dalen N, ~Ijern B: Bone mineral content in patients with primary: layperparathyroidism without radiological evidence of skeletal clmnges. Acta Endocrinol 75:297, 1974 9. Haas HG, Dambacher MA, GuncagaJ, et al: Renal effects of calcitonifi and parathyroid extract in man. J Clin Invest 50:2689, 1971 10. DeLnca HF: Vitamin D metabolism and function. Arch Intern ,Xled , 138:836, 1978 11. Holick MF, FronmterJ, McNeill S, et al: Photometabolism of 7-dihydrocltolesterol to previtamin D 3 in skin. Biochem Biophys Res Commun 76:107, 1977 12. Bhattacharyya MH, DeLuca ttF: The regulation of rat liver calciferol-25-bydroxylase. J Biol Chem 268:2969, 1973 13. Olson EB, Knutson JC, Bhattaclmryya MH, et ah The effect of hepatectom)" on the s)'nthesis of 25-hydroxyvitamin D 3. J Clin Invest 57:1213, 1976 14. Rasmussen H, Wong M, Bikle D, et al: Hormonal control of the renal conversion of 25-h)'droxycholecalciferol to 1,25dihydroxyclmlecalciferol. J Clin Invest 51:2502, 1972 15. DeLuca HF: Vitamin D--1973. A m J Med 57:1, 1974 16. Reynolds JJ, H01ick MF, DeLuca HF: The role of vitautin D metabolites in bone resorption. Calcif Tissue Res 12:295, 1973 17. Arnaud C, Rasmussen H, Anast C: Further studies on the interrelationship between parathyroid hormone and vitamin D . J Clin Invest 45:1955, 1966 18. Friedenstein AJ: Precursor cells of mechanoc)'tes, hat Rev Cytol 47:327, 1976 19. Friedenstein A: Determined and inducible osteogenic precursor cells. In Elliott K, Fitzsimmons D (eds): Hard Tissue Growth, Repair, and Remineralization. Ciba Foundation Symposium 1 I. Amsterdam, Elsevier, 1973, p 169 20. Parfitt AM, Villanueva AR, Matthews CttE, et al: Kinetics of matrix and mineral apposition in osteoporosis and renal osteodystrophy. Relationship to rate of turnover and to cell morphology. Metab Bone Dis 2S:213, 1980 21. Marotti G: Decrement in volume ofosteoblasts'during osteon formation and its effect on the size of the correspbnding osteocytes. In Meunier P ted): Bone Histomorphometry. Second International Workshop on Bone Morphology. Lyon, France, Armour Co, 1976, p 311 22. Belanger LF, Robichon J, Migicovsky BB, et al: Resorption without osteoclasts (osteol)'sis). In Sognnaes RF ted): Mechanisms of ttard Tissue Destruction, publ #75, American Association for tbe Advancement of Science, 1963 23. Rasmussen H, Bordier P: The celhdar basis of metabolic bone disease. N EnglJ Med 289:25, 1973 24. Weisbrode ST, Capen CC, Nagode L A : Influence of para-

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72. Malluche HH, Ritz E, Lange HP, et ah Bone histology in incipient and advanced renal failure. Kidney Int 9:355, 1976 73. Lumb GA, Mawer EB, Stanbury SW: The apparent vitamin D resistance of chronic renal failure. Am J Med 50:421, 1971 74. Cochran M, Platts MM, Moorhead PJ, et ah Spontaneous hypercalcaemia in maintenance dialysis patients: an association with atypical osteomalacia and fractures. Min Electrolyte Metab 5:280, 1981 75. Slatopolsky E, Caglar S, Pennell JP, et ah On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using "proportional reduction" of dietary phosphorus intake. Kidney Int 2:147, 1972 76. Teitelbaum SL, Bergfeld MA, FreitagJ, et ah Do parathyroid hormone and 1,25-dihydroxyvitamin D modulate bone formation in uremia? J Clin Endocrinol Metab 51:247, 1980 77. Hruska KA, Teitelbaum SL, Kopelman R, et ah The predictability of the histological features of uremic bone disease by non-invasive techniques. Metab Bone Dis 1:39, 1978 78. Hruska KA, Korkor A, Martin K, et al: Peripheral metabolism of intact parathyroid hormone. Role of liver and kidney and the effect of chronic renal failure. J Clin Invest 67:885, 1981 79. Slatopolsky E, Calgar S, PennellJP, et al: On the pathogenesis of hyperparathyroidism in chronic experimental renal osteodystrophy in the dog. J Clin Invest 50:492, 1971 80. Rutherford WE, Bordier P, Marie P, et al: Phosphate control and 25-hydroxycholecalciferol administration in preventing experimental renal osteodystrophy in the dog. J Clin Invest 60:332, 1977 81. Slatopolsky E, Gray R, Adams ND, et al: The pathogenesis of secondary hyperparathyroidism in early renal failure. In Norman AW, Schaefer K, von Herrath D, et al (eds): Vitamin D, Basic Research and Its Clinical Application. Berlin, Walter deGruyter, 1979, p 1209 82. Colodro IM, Brickman AS, Coburn JW, et al: Effect of 25hydroxyvitamin D3 on intestinal absorption of calcium in normal man and patients with renal failure. Metabolism 27:745, 1978 83. Brumbaugh PF, Haussler DH, Bressler R, et al: Radioreceptor assay for lct25-dihydroxyvitamin Ds. Science 183:1089 84. Eisman JA, Hamstra AJ, Kream BE, et ah 1,25-Dihydroxyvitamin D in biological fluids: a simplified and sensitive assay. Science 193:1021, 1976 85. Weinstein RS: Decreased mineralization in hemodialysis patients after subtotal parathyroidectomy. Calcif Tissue Int 34:16, 1982 86. Ellis HA, McCarthy JH, Herrington J: Bone aluminum in haemodialyzed patients and in rats injected with aluminum chloride: relationship to impaired bone mineralisation. J Clin Pathol 32:832, 1979 87. Ott SM, Maloney NA, Coburn JW, et ah The prevalence of bone aluminum deposition in renal osteodystrophy and its relation to tile response to calcitriol therapy. N EnglJ Med 307:709, 1982 88. Cann CE, Prussin SG, Gordan GC: Aluminum uptake by parathyroid glands. J Clin Endocrinol Metab 49:543, 1979 89. Morrissey J, Rothstein M, Mayor G, et ah Suppression of parathyroid hormone secretion by aluminum. Kidney Int 23:699, 1983 90. Kaehny WD, Aifrey AC, Holman RE, et al: Aluminum transfer during hemodialysis. Kidney Int 12:361, 1977 91. Kaehny WD, Hegg AP, Alfrey AC: Gastrointestinal absorption of aluminum from aluminum-containingantacids. N EnglJ Med 296:1389, 1977 92. JowseyJ: Calcium release from the skeletons of rachitic puppies. J Clin Invest 51:9, 1972 93. Bar-Shavit Z, Kahn AJ, Teitelbaum SL: Defective binding of macrophages to bone in rodent osteomalacia and vitamin D deficiency. J Clin Invest 72:526, 1983 94. Krukowski M, Kahn AJ: Inductive specificity of mineralized

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chronic renal insufficiency. Skeletal response. JAMA 235:164, 1976 Bordier P, VingraffJ, GuerisJ, et al: The effect of lct(OH)D 3 and lcq25(OH)2D3 on the bone in patients with renal osteodystrophy. Am J Med 64:101, 1978 Russell JE, Roberts ML, Teitelbaum SL, et ah The therapeutic effects of 25-hydroxyvitamin D3 on renal osteod)'strophy. Biochemical and morphometric analyses. Min Electrolyte Metab 1:129, 1978 Maloney NA, Ott SM, Alfrey AC, et al: Histological quantiration of aluminum in iliac bone from patients with renal failure. J Lab Clin Med 99:206, 1982 Brown DJ, Dawborn JK, Ham KN, et al: Treatment of dialysis osteomalacia with desferrioxamine. Lancet 2:343, 1982