Pathophysiology of Osteoporosis

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Bröll H, Dambacher MA (eds): Osteoporosis: A Guide to Diaposis and Treatment. Rheumatology. Basel, Karger, 1996, vol 18,pp 12-27

Pathophysiology of Osteoporosis Klaus Klaushofer, Meinrad Paerlik Ludwig Boltzmann Institute for Osteology, 4th Medical Department, Hanusch Hospital, Vienna, and Department of General and Experimental Patholory, University of Yienna

Medical School, ViennA Austria

Involutional (primary) osteoporosis is the manifestation of a metabolic bone disease in which the amount of normally mineralized bone matrix in affected patients has been reduced to a level below that of the normal population of the same age and sex. The disease is certainly of multifactorial origin, since genetic [1, 21, mechanical [e.9., 3], nutritional [e.9., 4] and hormonal factors [e.g., 5] can cause the severe impairment of the bone remodeling process [cf. 6] which is underlying the observed reduction of bone mass as well as the microarchitectural deterioration ofbone tissue, consequently leading to an increased risk offractures at typical sites of the skeleton. The distinct spatial and temporal pattern of bone remodeling is not only the result of homeostatic control of calcit m and inorganic phosphate metabolism by socalled calcium-regulating hormones but is also achieved by a locally coordinated action of a number of hormonal mediators, growth factors and cytokines on bone cell function. Pathophysiology of osteoporo' sis has, therefore, to deal with the great variety ofcauses that could lead to alterations in the activity of those factors, and, furthermore, has to consider any impact resulting therefrom on a possible disturbance of the bone remodeling process.

Extlaskeletal Regulation of Cdcium Homeostasis

After cessation of longitudinal skeletal growth, bone can still acquire additional mass and mineral density until a peak is reached between 30 and 35 years of age. From then on, bone mass is invariably declining. Physiologically, involution of mineralized bone leads to osteopenia, which describes the phenomenon of reduced bone mass and bone mineral density with advancing age. It is thus

Rheumatology

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obvious that not only the rate of involutional bone loss but also the amount of total bone mass at the time of peak skeletal development,i.e., at the starting point of the involutional process, are critical factors in determining the extent of bone loss and of mineral density reduction in later life periods [see e.g. 7]. Bone mineral density eventually depends on the extent to which calcium (and phosphate) acquired from exogenöus sources are deposited in mineralized form in bone tissue. Hence, dietary intake of calcium and the extent of fractional absorption in the small intestine through the period of skeletal development must play a key role for acquisition of an optimal bone mass. There is evidence [8, 9]

that better calcium nutrition during adolescence may optimize, within genetic boundaries, peak bone mass. Conversely, it is obvious that low levels of calcium intake and absorption, or in other words, a negative calcium balance prevailing over a prolonged period of time, by exerting a demand for calcium on the skeletal system, accelerates bone loss and is therefore detrimental for acquisition and maintenance of a sufficient bone mass and mineral densitv. Intestinal Absorption of Calcium In man, like in many other species, the small intestine is the most active site of calcium absorption whereas the large bowel is only of minor significance in this respect [see e.g. 10, I l]. One important factor which limits the efficiency of intestinal absorption of calcium is its availability as'free'calcium ion. In this respect, one has to consider that, on the one hand, the alkaline milieu, which prevails in almost the entire small intestine, facilitates precipitation of calcium, mainly in form of insoluble calcium hydroxyphosphates, but that on the other hand, a number of organic compounds, which are ingested with or produced by the digestive process from food, or are constituents of digestive fluids, such as citric acid, mono- and disaccharides (e.g., fructose, mannose, mannitol, sorbitol and lactose), amino acids (Llysine, Larginine) or di- and trihydroxy bile acids, are able to prevent precipitation through formation of soluble calcium complexes and thereby increase the availability of calcium. The positive effect of bile acids on the calcium absorptive process can be inferred from the observation in a number of species that severed bile acid secretion causes a substantial reduction of calcium uptake from the Iumen of the small intestine [cf. 12]. However, a number of other food constituents do not increase but rather reduce the availability of calcium. For instance, oxalic acid, which is abundant in spinach, rhubarb, turnips or red beets, or phytic acid, which is contained mostly in cereal products, form complexes with such a high afhnity that calcium becomes unavailable for transfer out of the intestinal lumen. Calcium can be delivered from the intestinal lumen to the circulation either on a transcellular or on a paracellular route. Transfer across the enterocyte is a

Pathophysiology of Osteoporosis

vectorial multistep process which encompasses (a) calcium entry across the brushborder membrane probably via calcium channels, (b) intracellular diffusion (facilitated by the vitamin D-dependent calcium-binding protein, calbindin), and (c) extrusion across the basolateral aspect of the cell primarily via an ATP-driven calcium pump (Ca2+-ATPase) and possibly also through a Na*/Ca2* exchange mechanism. Overall transcellular calcium transport exhibits saturation kinetics and is subject to regulation by the active vitamin D metabolite, 1,25-dihydroxyvitaminD3 (1,25-dihydroxycholecalciferol, calcitriol, 1,25(OH)zD:) [forreview, see 13]. Yitamin D deficiency almost completely abolishes saturable transcellular calcium absorption [for details, see 14]. Under these circumstances only nonsaturable calcium transport can be observed which probably proceeds on a paracellular route. This involves certainly migration through intercellular 'tight' junctions and very likely also transfer of calcium via specific transcytotic processes. It should be mentioned that there is evidence that uptake of calcium from the small intestinal lumen into endocytotic vesicles can be mediated by a so-called nongenomic effect of 1,25(OH)2D3 [15]. The relative contribution ofparacellular transport to total calcium absorption shows large variations (between 20 and 1000/0) dependent on the anatomical location, the vitamin D status of the organism and the luminal calcium concentra-

tion. Thus, paracellular calcium transport is dominant in the distal part of the small intestine, particularly when transcellular calcium transport is down-regulated (as in old age) orwhen the food content ofcalcium is abundant [16-18]. It seems clear that a number of variables determines the efficiency of calcium absorption. Therefore, it is not surprising that the fractional absorption of calcium from the diet can vary between 25 and 700/o lL9l. Under certain circumstances it is desirable to increase intestinal absorption of calcium, namely, to achieve an adequate bone mass and mineral density in young adult age as part of a strategy to prevent osteoporosis, or to slow down bone loss after manifestation of the disease. In this respect one has to consider the fact that fractional absorption of calcium does not increase linearly with increasing calcium concentrations. The reason for this lies in the fact that at a normal vitamin D status, fractional absorp-

tion of calcium is subject to feedback regulation by circulating levels of 1,25(OH)2D3 (for details, see later). When calcium supply is low, this mechanism guarantees an adaptive increase in calcium absorption by expanding the saturable component ofthe absorptive process, but, conversely, at high dietary calcium a

corresponding decrease in saturable calcium transfer attenuates total absorption. Malabsorption of calcium in the elderly has been well documented [see e.g.

16,20-23). The decrease of calcium absorption with advancing age might be exp[ained by a general incapacitation of the instestinal mucosa to absorb nutrients, or more importantly by an age-related decline in the biosynthesis of 1,25(OH)2D3 leading to reduction of calcium transfer on the vitamin D-induced

Klaushofer/Peterlik

transcellular pathway. Since calcium malabsorption due to mild vitamin D deficiency has been implicated in the pathogenesis of type I ('postmenopausal') and particularly oftype II ('senile') osteoporosis [5], correction ofthe defect in calcium absorption by administration of vitamin D is a reasonable approach for treatment of osteoporosis. However, it must be noted that there is evidence from animal studies that in old age not only calcium absorption is decreased but also the capacity to adapt to a low calcium diet [20]. That means that calcium supplementation

in addition to vitamin D administration is

necessary

to restore the calcium

absorptive capacity of the small intestinal mucosa. Oral calcium supplementation for prophylaxis and therapy of osteoporosis is met with some concern since, first, high levels of calcium intake were suspected to lead to pronounced hypercalciuria and consequently to an increased risk of urinary stone formation, and second, it is not clear whether at all or to which extent an increment in absorbed calcium can be integrated into the skeletal system. It should be noted, however, that in a recently published review it was concluded that 'in healthy individuals with no history of nephrolithiasis and who are not hypercalciuric, calcium supplements appear to be associated with minimal risk of nephrolithiasis, and may provide considerable benef,rt in reducing the risk of osteoporosis' [24]. This notion has certainly a physiological basis in the observation that even a large increment in calcium absorption in the intestine leads only

toamarginalenhancementofrenalcalciumexcretion[cf. 14,25].This,however, forces the conlcusion that, due to the characteristic features ofrenal calcium han-

dling, a relatively large amount of calcium absorbed

in the intestine is not

excreted in the urine and must therefore be available for the formation of mineralized bone.

Renal Handling of Calcium The role of the kidney in calcium homeostasis is primarily to conserve body calcium. Only a minute amount, approximately 0.5 06 of the total calcium cleared from plasma by glomerular filtration, is excreted in the urine [26]. Calcium reabsorption along the nephron shows a complex segmental pattern. More than 600/o of filtered calcium is reabsorbed in the proximal convoluted tubule. The thick ascending limb, the distal convoluted tubule and the collecting duct have been identiflred as further sites of eflicient calcium reabsorption. 1,25(OH)2D3 affects transcellular renal calcium transport mainly in the distal convoluted tubule 1cf.27,28], while parathyroid hormone (PTH) promotes passive calcium reabsorption in the thick ascending limb as well as in the late distal convoluted tubule and in the adjacent collecting duct [cf. 25,26]. Although renal calcium loss is not considered a prime cause of osteoporosis, hypercalciuria certainly cannot be excluded as one of the many factors contributing to the pathogenesis of the disease. In fact, a small but significant number of

Pathophysiology of Osteoporosis

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osteoporosis patients (about 190/o) [see 29] present with idiopathic hypercalciuria. In addition, hypercalciuria can occur as side effect of diuretic drug treatment and

may thus cause an aggravation of the disease, particularly when elderly patients with an already compromised skeletal balance, who also frequently suffer from cardiac disease, are being treated for this reason with certain diuretics. Furose-

mide and other'loop diuretics' inhibit calcium reabsorption in the medullary thick ascending limb [25] in contrast to thiazides, which reduce urinary calcium excretion by an as yet not completely deflrned mechanism. There is evidence from animal as well as clinical studies that a diet rich in protein enhances urinary calcium excretion [30, 31], the reason forwhich is largely unknown. One explanation could be that enhanced breakdown of proteins under this condition leads to accumulation of certain amino acids like arginine, which are known to stimulate secretion of insulin. The hormone, in turn, might then inhibit tubular reabsorption of calcium [32]. Thus, whenever unbalanced protein-rich diets are advocated, possible adverse effects on calcium balance have to be taken into consideration. The Vitamin D/PTH Axis and Extraskeletal Calcium Homeostasis Bone contains 990/o of total body calcium and is therefore its only storage pool within the organism. Maintenance of intracellular as well as extracellular calcium within an extremely small range is vital for normal cell and organ functions. If extracellular homeostasis cannot be achieved through absorption and reabsorption ofcalcium in the intestine or in the kidney, respectively, calcium has to be mobilized from its only storage pool, i.e. from bone. Thus, conservation of total bone mass and of adequate bone mineral density is stringently connected to eff,rcient regulation of calcium homeostasis at extraskeletal sites. In this respect, the optimal function of the vitamin D/PTH axis is of particular importance. Although osteoporotic patients show no overt signs of vitamin D deficiency or parathyroid gland dysfunction, relatively small changes in circulating levels of 1,25(OH)2D3 and/or of PTH, respectivley, have been implied in the pathogenesis of involutional osteoporosis [5].

Vitamin D. Sources for the most active vitamin D compound, 1,25-dihydroxyvitamin D3, iue endogenous vitamin D3 produced under the influence of UV light in the epidermis as well as exogenous vitamin D3 supplied with the diet. Bound to a specific vitamin D-binding protein (DBP) in the plasma, vitamin D3 is transferred to the liver, where it is converted to 25-hydroxyvitamin D3. This compound is further metabolized in the kidney either to 24,25-dihydroxyvitamin D3, to which no particular function in calcium and Pi homeostasis could be assigned as yet, or to l,25-dihydroxyvitamin D3, which is the biologically most active vitamin D compound [for review, see 33].

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on the molecular level, 1,25(oH)2D1acts like a steroid hormone, i.e. through receptor-mediated action on the genome of its target cells. In the enterocyte, 1,25(oH)2D3 promotes transcellular calcium transport through activation of the calcium-binding protein (caBP, now called calbindin) gene. This process comprises binding of 1,25(oH)2D3 to a high-affinity cytoplasmic receptor, interaction

of the hormone/receptor complex with a corresponding hormone response element in the 5'flanking region of the caBp gene, and subsequent increase in gene activity. The extent of CaBP synthesis controls the amount of calcium transferred across the enterocyte [for a detailed review on the role of CaBp in intestinal calcium absorption, see e.g. 131. similar considerations apply to the mode of 1,25(oH)2D3-induced calcium transfer across the renar epithelium which is most prominent in the distal convoluted tubule 127,281. Parathyroid Hormone. Although prH acts in concert with 1,25(oH)2D3 to maintain extracellular calcium levels, it does so at different sites and by a different mechanism. Despite occasional reports on a distinct effect of PTH on intestinal calcium transport, a clear-cut role of the enterocyte as target cell for prH

could never be established. In contrast, the renal tubular cell, since it contains specific membrane receptors for PTH, is apparently the prime taryet cell for the peptide hormone. The biological activity of the hormone resides entirely in its N-terminal portion (amino acids l-34). while receptor binding can be established through amino acids 3-34, only the complete l-34 peptide is able to activate the receptor and consequently trigger the signal transduction mechanism in which cAMP certainly plays a pivotal role. Despite numerous efforts, further steps in signal transduction leading to increased transepithelial transfer ofcalcium could never be clearly established. tt has been suggested that PTH could promote passive calcium transfer via cAMpmediated intracellular events that cause appropriate changes in the paracellular calcium permeability [34]. vitamin D/PTH Interactions. vitamin D and prH actions, though mediated by different cellular mechanisms, nevertheless, are indirectly connected, namely through mutual stimulation of each other hormone's biosynthesis. The regulatory loop formed thereby allows, on the one hand, rapid and effrcient adaptation of calcium absorption to the need of the organism, and, on the other hand, protects

the organism from the detrimental effects of elevated extracellular and consequently intracellular calcium levels. It must be emphasized that compensation of low plasma calcium levels is achieved not only by activation of intestinal and renal transfer mechanisms but, if necessary, also by mobilization of calcium from bone, which results from activation of osteoclastic resorption by prH. This should again emphasize the factthat integrity of bone structure can be preserved

Pathophysiology of Osteoporosis

over a long period of time only when a suflicient amount of calcium can be secured from extraskeletal sources. This of course can only be the case, if, for instance, intestinal absorption ofcalcium is not reduced as a result oflow dietary intake or of a compromised vitamin D status.

Hormonal Imbalances and Involutional Osteoporosis In fact, malabsorption of calcium due to mild vitamin D deficiency is a common finding in patients suffering from involutional osteoporosis, regardless whether the disease is of the postmenopausal type I or of the age-related type II. According to Melton and Riggs [5], these two subgroups can be defined on basis of differences in age of manifestation, sex ratio, prevalence of fracture sites and, most notably, with respect to calcemic hormone levels, differences in parathyroid function and in causes of disturbed vitamin D metabolism. Regardless whether classif,rcation ofosteoporosis as type I and II is adequate to account for the complexity of the disease, it is suggestive for two completely different ways of pathogenesis. In type I osteoporosis in women, the estrogen dehciency associated with the menopause is believed to greatly accelerate the agerelated involution of the skeletal mass. That means that appreciably more mineralized matrix disintegrates than that is formed and, consequently, during this process more calcium (and phosphate) than normal is released from bone. Ensuing depression ofparathyroid function leads to a (secondary) decrease in biosynthesis

of 1,25(OH)2D3. Pathogenesis oftype II ('senile') osteoporosis takes a quite different course. The prime cause in this case is believed to reside in the very process of aging with associated reduction of bone formation on the one hand, and decreased renal synthesis of 1,25(OH)2D3 on the other hand. In addition, vitamin D deficiency due to dietary habits and insuflicient exposure to sunlight (often as a consequence of immobilization) is a frequent f,rnding in the elder population [see e.g. 23]. Importantly, vitamin D defrciency per se or in combination with ensuing malabsorption ofcalcium causes secondary hyperparathyroidism [35], thus shifting the 'equilibrium'between bone formation and resorption even more to the latter.

Regulation of Bone Turnover For a better understanding how hormonal imbalances could cause a disarray of the bone remodeling process, insights are necessary into the diversity of bone cell functions and their linkage together via systemic and local regulatory factors [see 36].

Klaushofer/Peterlik

Bone Formation: Regulation of Osteoblast Functions

The major components of the extracellular matrix, which are synthesized by bone-forming cells, the osteoblasts, include chondroitin sulfate-containing proteoglycans, type I collagen, and noncollagen proteins such as bone sialoproteins and phosphoproteins as well as osteonectin and the vitamin K-dependent osteocalcin and matrix Gla protein [for review, see 37]. Formation of new bone is not simply a matter of deposition of organic matrix components in sufficient amounts but, particular§ with respect to mineralization, depends also on the timely induction of certain enzymes (such as alkaline phosphatase) and proteins which exhibit high affrnity for hydroxyapalite, e.9., osteocalcin or matrix Gla protein, and which, therefore, seem to play a crucial role in the process of mineralization. Bone formation must be viewed as a multistep process during which osteoblasts undergo transition from the proliferative to more differentiated states [see 38, 39].

1,2|-Dihydroxyvitamin D j. Yitamin D in its hormonally active form of 1,25dihydroxyvitamin D influences formation of mineralized bone in a dual manner: First, through stimulation of intestinal and probably also renal absorptive processes, the sterol is necessary to secure an adequate supply ofboth calcium and inorganic phosphate for mineralization of newly formed bone matrix (see before). Second, l,25-dihydroxyvitamin D3 profoundly influences ostoblast function by controlling the expression of certain genes in a differentiation dependent manner [38, 39]. Bone formation is initiated by proliferation of osteoblasts and production of extracellular matrix components. In osteoblast cell cultures, in this period collagen type I is expressed at its peak level under the influence of 1,25(OH)2D3. In the following period of extracellular matrix maturation, the hormone promotes transition into a more differentiated state as reflected by induction of alkaline phosphatase activity. Finally, during mineralization, the expression of three proteins which are instrumental for triggering the mineralization process, name§ osteocalcin, matrix Gla protein and osteopontin, is transcriptiona§ up-regulated by 1,25(OH)2D3.

Steroid Hormones. The importance of estrogen for the maintenance of normal bone mass has been recognized since decades as a result of numerous clinical observations [cf. 5]. However, the mechanism by which estrogens and also andro. gens could influence bone turnover remained an enigma until recently, since it was common belief that bone cells do not contain estrogen receptors. Thus the positive action of estrogen on bone structure was attributed to indirect effects of the hormone [40]. Calcitonin was considered a mediator of estrogen effects because low levels of the hormone found in osteoporosis patients could be raised by estrogen treatment [see e.g. 41]. However, direct evidence for the presence of

Pathophysiology of Osteoporosis

19

specific estrogen-binding sites in normal human osteoblast-like cells could be obtained recently [42]. Furthermore, of all other steroids, only testosterone crossreacted with these receptors. Both sex steroids were shown to elicit biological responses in osteoblastJike cells including increased expression of or G)-procollagen and transforming growth factor-B (TGF-ß) 143-451. In contrast to the sex steroids, glucocorticoids decrease procollagen type I mRNA levels [46] and thereby exhibit profound negative effects on osteoblast function. Growth Factors. Among the many growth factors which influence either bone

resorption or formation [for review, see 47], there are two which seem to be of particular importance for local regulation of bone formation, namely TGF-p and insulinJike growth factor (IGF)"I. Both are synthesized by skeletal cells, and, in addition, TGF-ß is also abundant in the extracellular matrix. TGF-ß is a potent mitogen for cells of the osteoblastic lineage, and, in addition, stimulates bone collagen synthesis. Similar§, IGF-I enhances proliferation of preosteoblasts and augments bone matrix synthesis in more differentiated osteoblasts. There is evidence for hormonal regulation of the synthesis of the two growth factors: While anabolic sex steroids induce TGF-P 144,451, expression of IGF-I is upregulated by PGE2 [48] and thyroid hormone [49]. Thus, TGF-B as well as IGF-I could serve as mediators of the stimulatory action of these hormones on bone formation. Fluoride. There is clinical evidence that fluoride can influence bone formation through activation of osteoblast functions. It has been shown in a number of studies that fluoride treatment of osteoporotic patients promotes deposition of osteoid in newly formed bone as a prerequisite for any increase in bone mineral density [see e.g. 50]. In vitro, fluoride increases osteoprogenitor cell proliferation, particularly in combination with other bone cell mitogens such as IGF-I [5 I ]. Bone Resorption: Regulation of Osteoclast Function

Although in the majority of cases of involutional osteoporosis, a decrease in the rate of bone formation seems to be the main reason for accelerated net loss of bone mass, enhanced resorption due to increased activity of osteoclasts must certainly be considered an important factor in the development of the disease. Osteoclasts are multinucleated giant cells, endowed with specialized organelles and plasma membrane structures to allow resorption of inorganic as well as organic matrix components. They are now being thought to originate from hematopoetic stem cells, which have the potential to differentiate either along the monocyte/macrophage or along the preosteoclast/osteoclast pathway. A great number of structurally unrelated factors is known to be able to recruit and to

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activate osteoclasts and therefore cause bone resorption in vitro and in vivo [52]. Those include calcium-regulating hormones (PTH, 1,25(OH)2D3), thyroid hormones, retinoic acid, prostaglandins (particular§ of the E and I series), factors acting at least partially through prostaglandins like the cytokines [53], IL6 growth (EGF, ILl l factors PDGF, TGF-P, inflamand thrombin), and [54] [55], matory mediators (e. g. bradykinin). In contrast to the great variety of systemic and local factors causing bone resorption, only calcitonin, estrogen and since recently also y-interferon are known as endogenous inhibitors of osteoclast activity.

ILI

Calcitonin. This peptide hormone, which is elaborated by parafollicular cells in the thyroid gland (C cells), was originally discovered by its ability to lower elevated serum calcium levels. Although there is experimental evidence that calcitonin can increase renal calcium excretion, it is still a matter of debate whether

this or any other effect of the hormone on extraskeletal calcium metabolism has any physiological signiflrcance for the regulation of calcium homeostasis. However, it is quite clear that calcitonin by interaction with high-aff,rnity receptors on the osteoclast plasma membrane is a potent inhibitor of osteoclastic bone resolption. The hallmark of calcitonin action is that activated osteoclasts lose their ruf-

fled border and consequently cease resorbing mineralized bone [for review, see 56]. Calcitonin, therefore, has the capacity to protect the skeleton from excessive calcium loss, particularly under conditions ofhigh calcium need and turnover such as during growth, pregnancy, or lactation.

Eslrogen. There is convincing evidence from clinical observations that estro gen deficiency causes enhanced bone resorption. Although this implies that, conversely, estrogen has an inhibitory effect on osteoclastic bone resorption, this hlpothesis could not be substantiated until recently, when the presence of a specific estrogen receptor, and, in addition, a receptor-mediated inhibition of osteoclast formation [57] and bone resorption was demonstrated in isolated osteoclasts 1581.

y-Interferon. Although this lymphokine like calcitonin is able to block the bone-resorbing action of activated osteoclasts [59], y-interferon could inhibit resorbing processes in additional ways. First, 7-interferon inhibits the recruitment of osteoclasts from undifferentiated precursors [e.g., 59], and, second and most importantly, it is a potent inhibitor of endogenous prostaglandin synthesis in bone [60]. Therefore, y-interferon inhibits the prostaglandin-mediated resorptive activity of a variety of factors such as interleukin-l [61], thyroid hormones [62], bradykinin [63], and thrombin [59]. Recently, 1-interferon was shown to completely block also the cAMP-dependent bone-resorbing action of PTH [64].

Pathophysiology of Osteoporosis

Bone Formation/ Resorption Coupling Although osteoporosis is certainly a systemic disease, it affects trabecular and cortical bone to a different extent at different sites ofthe skeleton, so that fractures arise only at few predilected sites such as vertebrae, proximal femur or distal

radius. This points to the importance of local dysregulation of bone turnover for the pathogenesis of involutional osteoporosis [36]. It must be emphasized that bone-resorbing agents, even if they are capable to recruit osteoclasts from bone marrow cells, nevertheless seem to activate osteoclasts only by indirect means. A great number of bone-resorbing factors were

shown

to act primarily on the osteoblast which,

e.g.

in

case

of PTH

or

1,25(OH)2D3, is the only type of bone cells endowed with specific membrane or cytoplasmic receptors for these calcemic hormones. It is assumed that through receptor-mediated mechanisms they inhibit typical osteoblast functions such as collagen production, induce secretion of osteoclast-activating cytokines, and cause retraction ofosteoblasts so that osteoclasts can adhere to and become activated in contact with the mineralized surface [62]. The sequence of events described above establishes a coupling mechanism between osteoblast and osteoclast functions. In fact, there is unequivocal evidence that in vitro osteoclasts are able to resorb mineralized bone only in the presence of osteoblasts [e.g., 66]. Of great importance in linking bone resorption to bone formation seems to be the dual role that prostaglandins play in bone remodeling [for review, see 67]. Prostaglandins, particularly of the E series, not only stimulate osteoclastic resorption, either directly or as mediators of other bone-resorbing agents, but are also capable of inducing bone formation, e.g. through induction of IGF-I expression in osteoblasts [48].

Another mechanism in coupling bone resorption to bone formation might involve PTH and TGF-p: PTH not only releases the growth factor from bone matrix but also enhances it binding to its osteoblast receptor [68] so that PTHinduced resorption could be compensated by TGF-p stimulation of osteoblast functions.

TGF-P not only stimulates bone formation but is also capable of inducing osteoclastic bone resorption [69], largely through generation ofendogenous pros-

taglandins. This must be considered another mechanism of bone formation/ resorption coupling. In this respect it should be emphasized that the effects of mechanical strain, which is necessary for effrcient formation/resorption coupling, are probably mediated by changes in activity of PGE2, IGF-I or TGF-p. Evidence is accumulating to indicate that the sensitivity of bone cells to mechanical stimuli depends largely on the presence ofestrogens [for review, see 70].

Klaushofer/Peterlik

It is interesting to note that a number of factors with known effects on bone formation or resorption, are also immune regulatory factors. Disturbances in bone remodeling could thus be also a consequence of altered local immune reactivity. In fact, among the calcium-regulating hormones, particularly 1,25(OH)2D3 can modulate proliferation and differentiated functions of immune cells (monocyteVmacrophages, B and T lymphocytes) [for review, see 71]. Conversely, a number of cytokines and lymphokines such as IL6 or [L11, which are important mediators of immune reactions, exhibit also profound effects on bone turnover 153-551. ILl, which is a potent stimulator of bone resorption [53], is secreted in larger amounts by peripheral blood monocytes from osteoporotic

[Ll,

patients than from cells derived from healthy controls [72]. IFN-y and IL-4, another T+elI cytokine, are both potent inhibitors of bone resorption 159,60,731. They are able to suppress the bone-resorbing action of calcium-regulating hormones as well as that of ILl. Both lymphokines are produced by, among others, also CD8+

T lymphocytes [cf. 74]. In postmenopausal (type I) osteoporosis, the

ratio of CD4+/CD8* T lyrnphocytes is increased mainly due to a reduction in absolute numbers of CD8* cells [75, 76]. Interestingly, this defect can be corrected by treatment with 1,25(oH)2D3 [75].

Primary and Secondary Osteoporosis - A Summary A number of factors or conditions can be implied in the pathogenesis of involutional, i.e. primary osteoporosis. Thus, within genetic boundaries, any lifestyle, dietary habit, hormonal imbalance as well as any chronic gastrointestinal and renal disease, which, alone or in combination, causes chronic disturbances of calcium metabolism and/or dissocation of bone formation/resorption coupling must be considered to increase the risk ofaccelerated bone loss. As far as systemic hormones are concerned, alterations in biosynthesis and secretion of 1,25(OH)2D3, PTH, or anabolic sex steroids, as mentioned before, have been implicated in the pathogenesis of involutional osteoporosis. Recently, also a cause for thyroid hormones as pathogenetic factors has been made by the observation that even in euthyroid osteoporotic patients serum triiodothyronine levels are inversely related to the extent of bone mineral density [77]. At the skeletal level, it is clear that imbalances of systemic hormones could negatively affect the process of bone remodeling, because balance between bone formation and resorption is normally achieved only by a highly complex interaction of several regulatory mechanisms which involve systemic hormones as well as locally acting growth factors and cytokines (TGF-B, IGF-I, II-l,II.4,II-6, IL11, IFN-1 etc.).

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23

The term 'secondary osteoporosis' is widely used to refer to those conditions in which decreased bone mass is associated with a specific disease or pharmacologic agent [for review, see e.g. 78,791. In any ofthese instances, osteoporosis can be traced to excess production or administration of a bone-resorbing agent (e.g., glucocorticoids, thyroid honnones, drugs etc.), or to deficiency of a factor which is normally required for optimal bone formation (calcium, vitamin D, estrogens and androgens, growth factors etc.). Accordingly, secondary osteoporosis (often together with osteomalacia) is observed, for instance, in Cushing's syndrome, hyperthyroidism, disturbances of vitamin D metabolism due to gastrointestinal liver and kidney disease, hypogonadism, calcium malabsorption, drug treatment with heparin, antiepileptics, etc. [79].

References

1 2 3 4 5 6 7 8 9

Seeman E, Hopper JL, Bach LA, Cooper ME, Parkinson E, McKay J, Jerums G: Reduced bone mass in daughters ofwomen with osteoporosis. N Engl J Med 1989;320:554-558. Morrison NA., Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA: Prediction ofbone density from vitamin D receptor alleles. Nature 1994;367:284-287 . Frost HM: Yital biomechanics: Proposed general ooncepts for skeletal adaptation to mechanical usage. Calcif Tissue Int 1 988;42: 145-1 56. Bronner F: Calcium and osteoporosis. Am J Clin Nutr 1994;60:831-836.

LI, Riggs BL: Clinical spectrum; in Riggs BL, Melton LI (eds): Osteoporosis: Etiology, Diagrosis and Management. New York, Raven Press, 1988, pp 155-179. Eriksen EF, Axelrod DW, Melsen F: Bone remodeling in metabolic bone disease; in: Bone Histomorphometry. NewYork, Raven Press, 1994, pp 51-59. MarcusR: Skeletalaging: Understandingthe functionaland structuralbasisofosteoporosis. Trends Endocrinol Metab 1 99 1 ;2:53-5 8. Sentipal JM, Wardlaw GM; Mahan J, Matkovic Y: Influence of calcium intake and growth indices on vertebral bone mineral density in young females. Am J Clin Nutr 199l;54:425-428. Johnston CC, Miller JZ, Slemenda CW, Reister TK, Hui S, Christian JC, Peacock M: Calcium supplementation and increases in bone mineral density in children. N Engl J Med 1992;327:82Melton

87.

10 11

Yergte-Marini P, Parker TF, Pak CY, Hull AR, Deluca HF, Fordtran JS: Jejunal and ileal calcium absorption in patients with chronic renal disease. J Clin Invest I 976;57:86 1-866. Barger-Lux MJ, Heaney RP, Recker RR: Time course of calcium absorption in humans: Evidence for

12 13 L4 15 16 17

a

colonic component. CalcifTissue Int 1989;44:308-31

l.

Lengemann FW, Dobbins JW: The role of bile in calcium absorption. J

Nutr 1958;66:45.

Bronner F: Intestinal calcium transport: The cellular pathway. Miner Electrolyte Metab 1990;16: 94-100. Sheikh MS, Schiller LR, Fordtran JS: In vivo intestfural absorption of calcium in humans. Miner

Electrollte Metab 1 990; 1 6: 1 30-1 46. Nemere I, Norman AW: Transcaltachia, vesicular calcium transport, and microtubule-associated calbindin-D2s;.: Emerging views of 1,25-dihydroxyvitamin D3-mediated intestinal calcium absorption. Miner Electrolyte Metab I 990; 1 6: I 09-l I 4. Ireland P, Fordtran JS: Effect of dietary calcium and age on jejunal calcium absorption in humans studied by intestinal perfusion. J Clin Invest 197 3:52.'2672-2681. Pansu D, Bellaton C, Bronner F: Development changes in the mechanism of duodenal calcium transport in the rat. Am J Physiol 1983;244:G20-G26.

Klaushofer/Peterlik

24

18 19 20 2l

Nellans HN: Intestinal calcium absorption; Interplay of paracellular and cellular pathways. Miner Electrolyte Metab I 990; I 6: 10 1-108. Bringhurst FR, Potts JT: Calcium and phosphate: Distribution, tumover and metabolic actions; in DeGroot LI (ed): Endocrinology. New York, Grune & Strattotr, 1979, vol2,pp 551-585. Armbrecht HJ: Effect ofage oncalcium and phosphate absorption: Roleof l,25-dihydroxyvitamin D. Miner Electrolyte Metab I 990; I 6: 1 59-l 66. Avioli LV, McDonald JE, Lee SW: The influence of age on the intestinal absorption of aTCa in women and its regulation to aTCa absorption in postmenopausal ostmporosis. J Clin Invest 1965;

44:1960-t967.

22

Bullamore, Gallagher JC, Wilkinson R, Nordin BEC: Effect of age on calcium absorption. Lancet

23

Gallagher JC, Riggs BL, Eisman J, Hamstra A, Arnaud SB, Deluca [IF: Intestinal calcium absorp tion and serum vitamin D metabolites in normal subjects and osteoporotic patients. J Clin lovest 1979;64:729-716. Ringe JD: The risk of nephrolithiasis with oral calcium supplementation (editorial). Calcif Tissue lnt 1991148:69-73. Brenner B, Coe FL, Rector FC: Calcium, phosphorus and magresium; in: Renal Physiology in Health and Disease. Philadelphia, Saunders, 1987, pp 153-183. Sutton RAL, Dirks JH: Renal handling of calcium: Overview; in Massry SG, Ritz E (eds): Phos phate Metabolism. New York, Plenum Press, 1977, pp 15-27. Bronner F, Stein WD: CaBP, facilitates intracellular diftrsion for Ca pumping in distal convoluted tubule. Am J Physiol 1988;255:F558-F562. Bronner F: Renal calcium transport: Mechanisms and regulation - An overview. Am J Physiol

1

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 4L 42

970;ii:535-537.

1989l,257:F70'7-F7ll. Whedon GD: Recent advances in management of osteoporosis; in Massry SG, Ritz E, Jahn H (eds): Phosphate and Minerals in Health and Disease. New York, Plenum Press, 1980, pp 597-613. Schuette SAo Linkswiler HM: Calcium; in Olson RE (ed): Present Kaowledge in Nutrition. Washington, The Nutrition Foundation Inc, 1984, pp 400-,1,09. Hegsted M, Linkswiler H: Iong-term effects of level of protein intake on calcium metabolism in young adult women. J Nutr l98l;lll:244-251. Wood RJ: Evidence for insulin involvement in arginine- and glucose-induced hypercalciuria in the rat. J Nutr 1983;1 l3:1561-1567. Fraser DR: Regulation of the metabolism of vitamin D. Physiol Rev 1980;60:551-613. BourdeauJE: Calciumtransport acrossthecorticalthickascendinglimb ofHenle'sloop; inBronner F, Peterlik M (eds): Calcium and Phosphate Transport across Biomembranes. New York, Academic Press, 1981, pp 199-202. Chapuy MC, Arllt ME, Dubceuf F, Brun J, Crouzet B, Amaud S, Delmas PJ, Meunier PJ: Vitamin D3 and calcium to prevent hip fractures in the elderly. N Engl J Med 1992;327:1637-1642. Raisz LG: lncal and systemic factors in the pathogenesis ofosteoporosis. N Engl J Med 1988;318: 8

I 8-828.

lJ

Robey PG, Fisher LW, Young MF, Termine JD: The biochemistry of bone; in Riggs LB, Melton (eds): Osteoporosis: Etiology, Diagnosis, and Management. New York, Raven Press, 1988, pp 95109.

Stein GS, Lian JB, Owen TA: Relationship of cell growth to the regulation of tissue-specific gene expression during osteoblast differentiation. FASEB J 1990;4:31 1 1-3123. Barone LM, Owen TA, Stein GS, Lian JB: Developmental expression and hormonal regulation of matrix gla protein (MGP) gene expression in mammalian osteoblasts and chondrocytes. J Bone Miner Res 1990;5(suppl 2):S74. Milhaud G, Christiansen C, Gallagher C, Reeve J, Seeman E, Chesnut C, Paditt A: Pathogenesis and treatment ofpostmenopausal osteoporosis. CalcifTissue Int 1983;35:708-71 1. Cano RP, Montoya MJ, Monrno R,Yazqtez A, Galan F, Garrido M: Calcitonin reserve in healthy women and patients with postmenopausal osteoporosis. CalcifTissue Int 198*45:203-208. Eriksen EF, Colvard DS, Berg NJ, Graham ML, Mann KG, Spelsberg TC, Riggs BL: Evidence of estrogen receptors in normal human osteoblast-like cells. Science 1988;241:8,1-86.

Pathophysiology of Osteoporosis

25

43 44 45

46 47 48

C, FroeschER: Enhancedosteoblast proliferation andcollagengene expression by estradiol. Proc Natl Acad Sci USA 1988;85:2307-2310. Komm BS, Terpening CM, Benz DJ, Graeme KA, Gallegos A, Korc M, Greene GL, O'Malley BW, Haussler MR: Estrogen binding, receptor mRNA, and biologic response in osteoblast-like osteosarcoma cells. Science 1988;241:81-84. Benz DJ, Haussler MR, Thomas MA, Speelman B, Komm BS: High-affrnity androgen binding and androgenic regulation ofol(I)-procollagen and transforming growth factor-p steady-state messenger ribonucleic acid levels in human osteoblastJike osteosarcoma cells. Endocrinology l99l;128.'27232730. Oikarinen AI, Uitto J, Oikarinen J: Glucocorticoid action on connective tissue: From molecular mechanisms to clinical practice. Med Biol 1986;64:221-230. Canalis E, McCarthy T, Centrella M: Growth factors and the regulation of bone remodeling. J Clin Invest I 988;8 I :277-28 l. McCarthy TL, Centrella M, Raisz LG, Canalis E: Prostaglandin E2 stimulates insulin-like growth factor 1 synthesis in osteoblast-enriched cultures from fetal rat bone. Endocrinology 1991:128:

ErnstM, Schmid

2895-2900.

49

Klaushofer K, Yarga F, GlantschrigH,Fratzl-Zelman N, Czerwenka E, Leis HJ, Koller K, Peterlik M: The regulatory role of thyroid hormones in bone cell growth and differentiation. J Nutr, in press.

50 51 52 53 54 55 56 57 58 59 60 61 62 63

Farley SMG, Libanati CR, Mariano-Menez R, Tudtud-Hans LA, Schulz EE, Baylink DJ: Fluoride therapy for osteoporosis promotes a progressive inrease in spinal bone density. J Bone Miner Res 1990;5(suppl l):S37-542. Farley JR, Tarbaux N, Hall S, Baylink DJ: Mitogenic action(s) of fluoride on osteoblast line cells: Determinants of the response in vitro. J Bone Miner Res 1990;5(suppl 1):S107-S113. Vaes G: Cellularbiology and biochemicalmechanism ofbone resorption. Areview ofrecent developments on the formation, activation, and mode of action of osteoclasts. Clin Orthop Relat Res 1988;231:239-27 l. Gowen M, Wood, PD, Ihrie ET, McQuire MKB, Russel RGG: An interleukin l-like factor stimulates bone resorption in vitro. Nature 1983;306:378-380. Jilka RL, Hangoc G, Girasole G, Passeri G, Williams D, Abrams J, Broxmeyer H, Manolagas SC: Increased osteoclast development after estrogen loss: Mediation by interleukin 6. Science 1992;257: 88-9 1. Girasole G, Passeri G, Jilka RL, Manolagas SC: Interleukin 1 1: A new cy'tokine critical for osteoclast development. J Clin Invest 1994:93:.1516-1524. Copp DH: Calcitonin comparative endocrinology; in DeGroot L (ed): Endocrinology. New York, Grune & Stratton, 1979,vol2,pp 637-645. Schiller C, Redlich K, Pietschmann P, Peterlik M: Multihormonal effects on osteoclast formation: Role of IL6. Bone 1995;16:401. Oursler MJ, Osdoby P, Pyfferoen J, Riggs LB, Spelsberg TC: Avian osteoclasts as estrogen target cells. Proc Natl Acad Sci USA 1 99 1 ;88:66 1 3-66 1 7. Klaushofer K, Hörandner H, Hoffmann O, Czerwenka E, König U, Koller K, Peterlik M: Interferon-y and calcitonin induce differential changes in cellular kinetics and morphology ofosteoclasts in cultured neonatal mouse calvaria. J Bone Miner Res 1989;4:485-606. Peterlik M, Hoffmann O, Swetly P, Klaushofer K, Koller K: Recombinant y-interferon inhibits prostaglandin-mediated and parathyroid hormone-induced bone resorption in cultured neonatal mouse calvaria. FEBS Lett 1985;185:287-290. Hoffmann O, Klaushofer I( Gleispach H, Leis HJ, Luger T, Koller I( Peterlik M: Gamma-interferon inhibits basal and interleukin-l-induced prostaglandin production and bone resorption in neonatal mouse calvaria. Biochem Biophys Res Commun 1987;143:38-43. Klaushofer K, Hoffmann O, Gleispach H, kis HJ, Czerwenka E, Koller K Peterlik M: Bone resorbing activity of thyroid hormones is related to prostaglandin production in neonatal mouse calvaria. J Bone Miner Res 1989;4:305-312. Lemer UH, Ljunggren Ö, Ransjö M, Klaushofer K, Peterlik M: Inhibitory effects of y-interferon on bradykinin-induced bone resorption and prostaglandin formation in cultured mouse calvarial bones. Agents Actions 1 99 l;32:305-3

Klaushofer/Peterlik

1

l.

26

64 65 66 6'l 68 69 70 7l 72 71 74 75 76 77 78 79

I! Hoffmann O, Peterlik M: On the role of cyclic AMP as a mediator of bone resorption: y-interferon completely inhibits cholera toxin- and fonkolin-induced but only partially inhibits parathyroid hormonestimulated a5Ca release from mouse calvarial bones. J Bone Miner Res 1991;6:551-560. Rodan GA, Martin TJ: Role of osteoblasts in homronal control of bone resorption - A hypothesis. I*mer UH, Ransjö M, Ljunggren Ö, Klaushofer

Calcif Tissue Int 198 1;33:349-35 1. McSheehy PMJ, Chamben TJ: Osteoblastic cells mediate osteoclastic responsiveness to parathyroid hormone. Endocrinology I 986; I I 8: 824-82 8. Raisz LG: The role of prostaglandins in the local regulation of bone metabolism; in Peterlik M, Bronner F (eds): Molecular and Cellular Regulation of Calcium and Phosphate Metabolism. New York, Wiley Liss, 1990, pp 195-203. Centrella M, McCarthy TL, Canalis E: Parathyroid hormone modulates transforming gowth factor p activity and binding in osteoblast-enriched cell cultures from fetal rat parietal bone. Proc Natl Acad Sci USA 1988;85:5889-5893. Tashjian AH, Yoelkel EF, I azzs16 M, Singer FR, Roberts AB, Derynck R, Winkler ME, kvine L: a and p human transforming growth factors stimulate prostaglandin production and bone resorption in cultured mouse calvaria. Proc Natl Acad Sci USA 1985;82:4535-4538. Rodan GA: Mechanical loading, estrogen deficiency, and the coupling ofbone formation to bone resorption. J Bone Miner Res 199l;6:527-530. Rigby WFC: The immunobiology of vitamitr D. Immunol Today 1988;9:54-58. Pacifici R, Rifas L, Teitelbaum S, Slatopolsky E, McCracken R, Bergfeld M, Lee W, Avioli LV, Peck WA: Spontaneous release of interleukin I from human blood monocytes reflects bone formation in idiopathic osteoporosis. Proc Natl Acad Sci USA 1987;84:4616-4620. Watanabe Tanaka Y, Morimoto I, Yahata Zeki K Fujihira T, YaEashita U, Eto S: Interleukin-4 as a potent inhibitor ofbone resorption. Biochem Biophys Res Commun 1990;172:L035-

Il

Il

1041.

Lewis DB, Yu CC, Meyer J, English BK" IQhn SJ, Wilson CB: Cellular and molecular mechanisms for reduced interleukin 4 and interferon-y production by neonatal T cells. J Clin Invest 1991;87:

19+202. Fujita T, Matsui T, Nakao Y, Watanabe S: T lymphocyte subsets in osteoporosis: Effect of lchydroxyvitamin D3. Miner Electrolyte Metab 1984;10:37 5-37 8. Imai Y, Tsunenari T, Fukase M, Fujita T: Quantitative bone histomorphometry and circulating T lymphocyte subsets in postmenopausal osteoporosis. J Bone Miner Res 1990;5:393-399. Schoutens A, Laurent E, Markowicz E, Lisart J, De Maertalaer Y: Serum triiodothyronine, bone turtrover, and bone mass changes in euthyroid pre- and postmenopausal women. CalcifTissue Int 1991;49:95-100. Raisz LG: Pathogenetic mechanisms of secondary osteoporosis; in Bronner F, Peterlik M (eds): Extra- and Intracellular Calcium and Phosphate Regulation: From Basic Research to Clinical Medicine. Boca Raton, CRC Press, l992,pp 129-136. Steflr PH: Side effects of drugs on bone; in Bronner F, Peterlik M (eds): Extra- and Intracellular Calcium and Phosphate Regulation: From Basic Research to Clinical Medicine. Boca Raton, CRC Press, 1992, pp 119-128.

Dr. Meinrad Peterlik, Institut Iür allgemeine und experimentelle Pathologie, Neubau AKH, Währinger Gürtel 1 8-20, A- 1 090 Yienna (Austria)

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