Adynamic Bone and Chronic Renal Failure: An Overview

JORGE B. CANNATA AND IA, MD, PHD

ABSTRACT: Renal osteodystrophy may present with a wide spectrum of bone lesions, ranging from high bone turnover to low bone turnover. Decreased serum calcium and 1,25-dihydroxy vitamin D synthesis and retention of phosphate are involved in the pathogenesis of high bone turnover. However, several factors may influence the evolution of this disorder. The use of different therapeutic approaches (such as calcium supplements, phosphate binders, vitamin D metabolites, etc.), the type of treatment (either hemodialysis or continuous ambulatory peritoneal dialysis), and also the changes in the type of patients to whom we are offering dialysis (more

diabetics and older patients are currently included in dialysis programs) may have introduced changes modifying the form of presentation of the bone metabolic disorders. As a result, recent studies reported a greater prevalence of adynamic forms of renal osteodystrophy. Patients with adynamic bone (with or without aluminum) would have more difficulties in handling and buffering calcium loads; consequently, they would have a higher risk of extraosseous calcifications. KEY INDEXING TERMS: Adynamic bone; Low bone turnover; Aluminium-induced disease; Hypoparathyroidism [Am J Med Sci 2000;320(2):814.]

one disease in patients with renal failure is a complex metabolic disorder. Despite predictable endocrine and renal excretory derangements, alterations in bone metabolism vary widely with the severity of renal failure and affect patients with unpredictable intensity.13 Hypocalcemia, diminished 1,25-dihydroxy vitamin D synthesis, and retention of phosphate trigger the development of secondary hyperparathyroidism. Nevertheless, other factors contribute to the clinical expression and degree of severity of this disorder. These include the nature of the underlying renal diseases, such as diabetes mellitus, and the influence that a type of therapy (eg, corticosteroids) may exert on some particular forms of bone lesions. In addition, the management of secondary hyperparathyroidism, for example the use of calcium supplements, phosphate binders, and vitamin D metabolites, and the dialysis treatment [hemodialysis or continuous ambulatory peritoneal dialysis (CAPD)] itself may influence clinical manifestations and severity of bone disease.4

From the Bone and Mineral Research Unit, Instituto Reina Sofia de Investigacio n, Hospital Central de Asturias, Universidad de Oviedo, Asturias, Spain The studies on low bone turnover in chronic renal failure have been partly supported from Fondo de Investigaciones Sanitarias (FIS 94/1901 E) and Fundacio n Renal In igo Alvarez de Toledo. Correspondence: Dr. Jorge B. Cannata And a, Metabolismo Oseo y Mineral, Instituto Reina Sof a de Investigacio n, Hospital Central de Asturias, c/Julian Claveria, s/n, 33006 Oviedo, Asturias, Spain (E-mail: metoseo@hca.es).
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Consequently, renal osteodystrophy represents a wide spectrum of bone derangements, ranging from high bone turnover, the commonest bone disturbance in chronic renal failure, to low bone turnover.5 8 Low bone turnover osteodystrophy reflects the lack of capacity to produce and mineralize bone matrix and has two main histological forms: osteomalacia and adynamic bone disease. In osteomalacia, the osteoid formation (osteoblast activity) is reduced but the main problem is deeply altered mineralization that increases nonmineralized osteoid (osteoid accumulation) and increases osteoid volume. By contrast, adynamic bone is characterized by a reduced osteoid formation with a proportional reduction in bone mineralization.9 11 To differentiate osteomalacia from adynamic bone, the cut-off levels that distinguish normal from abnormal osteoid volume are critical. The upper limit of normal osteoid volume is considered to be around 5% of total bone volume; however, influential studies have used different limits for defining normal osteoid volume (ranging from 5 to 15%), making it difficult to compare results among different publications.5 8,12 To best understand and manage adynamic bone disease it is necessary to consider its two main forms: (1) aluminum-induced and (2) nonaluminum-induced. The prevalence and incidence of adynamic bone (mainly nonaluminum-induced) is increasing, accounting for almost half of the bone lesions observed in some series.5,6 On the other hand, the frequency of what was previously the most common form of aluminum-induced, low bone turnover disease, aluminum-induced osteomalacia, is 81

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falling.6,7,13 A reduction in aluminum exposure seems mainly responsible for this change; unfortunately, effective reduction in exposure to aluminum has not been possible worldwide. Aluminum-induced adynamic bone and osteomalacia still are frequent diagnoses, particularly in developing countries.12,14 NonAluminum-Induced Low Bone Turnover More diabetics and older patients are currently on dialysis programs and this has increased the prevalence of nonaluminum-induced forms of adynamic bone.15 Early reports showed that diabetic patients have lower incidence of hyperparathyroidism and only moderate increase in bone activity;16 this has been corroborated experimentally.17 Factors that are likely to be involved in the reduced response of the parathyroid glands in diabetes include vascular disease of the parathyroid gland16 and the metabolic effects related to hyperglycemia and insulin deficit.17,18 Bone turnover decreases with age and may be an independent factor in the pathogenesis of low bone remodeling; it is very likely that parathyroid and bone cells, and their receptors, have diminished response capacity or reduced sensitivity in older patients.4 The various drugs used in the management of secondary hyperparathyroidism may play a role in increased prevalence of adynamic bone. Although initially the influence of calcium salts was deemed minor, recent reports have demonstrated higher levels of serum calcium, and higher intake of calcium salts in patients with adynamic bone.5,7 The use of calcitriol may also be considered in the pathogenesis of adynamia. This active vitamin D metabolite can suppress PTH indirectly by raising serum calcium and directly by its action on vitamin D receptors on the parathyroid gland.19 In addition, intermittent pulses of calcitriol may have a direct suppressive effect on bone through mechanisms not fully understood.20,21 Calcitriol promotes the differentiation of osteoblastic precursors into mature osteoblasts, enhances alkaline phosphatase and osteocalcin activity, but reduces collagen synthesis.20,22 Hypophosphatemia can also be involved in the pathogenesis of low bone turnover by reducing PTH secretion. Lower serum phosphate levels have been blamed for adynamic bone in CAPD patients. CAPD patients have higher serum calcium levels and more stable control of acidosis, which may lead to a higher incidence of adynamic bone.23,24 Furthermore, a greater proportion of diabetics and older patients receive CAPD treatment compared with hemodialysis.24 The increasing use of bicarbonate instead of acetate as a buffer in hemodialysis is another important factor.25 Acidosis increases bone resorption26; thus, bicarbonate use with the consequent better control 82

of acidosis may have contributed toward reducing the risk of high bone turnover.4 Low levels of estrogens, androgens, and thyroid hormones can also induce low bone turnover; however, these are less frequent causes of adynamic bone disease in renal patients. More important is the role of corticosteroids and other immunosuppressors, such as cyclosporin, currently used in patients who have organ transplants. The worldwide increase in the number of renal transplants has increased the number of patients on immunosuppressors that are placed on dialysis therapy. Longtime transplant survivors are exposed to immunosuppression longer and have a higher risk of having bone loss as a result of the effect of these drugs on bone metabolism.27 Additional factors such as cytokines, gene polymorphisms, and changes in the expression of receptors involved in bone metabolism, have been involved in the pathogenesis of renal osteodystrophy.4 Aluminum-Induced Low Bone Turnover Aluminum alters bone metabolism by a direct effect on bone or by indirectly inhibiting parathyroid hormone (PTH) function. Aluminum is toxic to bone because it accumulates in the mineralization front. Its presence between the osteoid and the mineralized bone is a physicochemical obstacle for calcium accretion,28,29 but it also impairs cellular proliferation and the activity of bone cells.30 32 Aluminium is also able to reduce PTH function and alter bone remodeling.29,33 Two main pathways for these effects have been implicated, a direct effect on parathyroid synthesis, degradation or release (which may be the most important mechanism), and an indirect effect by raising serum calcium, thus suppressing parathyroid activity.33,34 Regardless of which of the two is involved, reduction in the serum PTH levels is critical in favoring the appearance of adynamic bone.9 Bone toxicity can be attributed to aluminum only when great concentrations are found in the mineralization front, but its inhibitory effect on PTH function is not always taken into account and may be responsible for the low bone turnover in some forms of adynamic bone. The poor outcome observed after parathyroidectomy in some patients with aluminum overload supports this concept.30,35 Aluminum is considered responsible for low bone turnover when histochemical staining techniques using aurintricarboxylic (aluminon) show its presence in 25 to 30% of the trabecular bone surface.5,11,36 This histochemical approach has limitations. The aluminum-staining method with aluminon is specific but not sensitive enough.37 A more sensitive method, solochrome of azurine, revealed that the percentage of bone surface covered by aluminum is almost twice that observed with aluminon.37 Thus, the role of aluminum in the
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Cannata And a

pathogenesis of adynamic bone may have been underestimated heretofore.57,38 Aluminum is not the only metal implicated in the pathogenesis of low bone remodeling. Iron, which shares some biochemical and biological pathways with aluminum, may also favor the appearance of adynamic bone39 41; preliminary results suggest that strontium may induce low bone turnover as well.42 In summary, numerous factors may contribute to increase the frequency of adynamic bone in chronic renal failure. Some may act as facilitators, creating a more propitious background for low bone remodeling. Others may have independent and powerful direct effects on bone turnover. Parathyroid Function in Adynamic Bone Uremia is a state of multifactorial bone resistance (skeletal resistance) to the action of PTH. In chronic uremia, higher levels of circulating PTH are required to obtain an adequate (normal) bone turnover. By contrast, low bone turnover is currently associated with relative deficiency of basal PTH levels,43,44 because the levels are insufficiently increased to maintain an adequate bone turnover. The level of serum PTH necessary to obtain a normal bone turnover in dialysis patients ranged between 120 and 250 pg/mL; PTH concentrations lower than 120 pg/mL provide a positive predictive value of 90% for the diagnosis of low bone turnover.6 PTH deficiency in adynamic bone suggests that parathyroid gland function and response is inadequately low. In support of this suggestion, patients having adynamic bone show a reduction in the sensitivity of the parathyroid cells, independent of the presence of aluminum, although the percentage of maximal and minimal secretory capacities of the parathyroid gland remains in the normal range. On the other hand, patients with adynamic bone exhibited an altered capacity to handle calcium loads, since they had more sustained hypercalcemia after calcium infusions.45 These findings indicate that patients with adynamic bone (with or without aluminum) would have impaired handling and buffering of calcium loads and a higher risk of extraosseous calcifications.4,46,47 Adynamic bone or any other form of low bone remodeling suggests the possibility of mechanical incompetence and a higher risk of fractures. However, this constellation of problems has been observed consistently only in those forms of adynamic bone related to aluminum in which bone pain, hypercalcemia, and bone fractures are frequent. The presence of signs or symptoms is less frequent in nonaluminum forms of adynamic bone. In conclusion, low bone turnover is not a single entity and should not be always considered a disease. Low bone turnover, particularly adynamic
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bone, represents a useful description of a common form of skeletal response to different factors, including those related to chronic renal failure. Acknowledgments I thank P. Cannata Ortiz and M. J. Cannata Ortiz for help in the preparation of the manuscript. References
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