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REVIEW ARTICLE
Year : 2007  |  Volume : 17  |  Issue : 4  |  Page : 150-159
 

Pathogenesis and management of renal osteodystrophy


1 Department of Medicine, Armed Forces Medical College, Pune, India
2 Command Hospital (CC), Lucknow, India
3 Command Hospital (SC), Pune, India

Correspondence Address:
A S Narula
Department of Medicine, Armed Forces Medical College, Pune
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-4065.39168

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  Abstract 

Renal osteodystrophy is a common complication of chronic kidney disease (CKD). It is the part of a broad spectrum of disorders of mineral and bone metabolism that develop in this clinical setting and result in both skeletal and extraskeletal consequences. Insights into the mechanisms of bone remodeling, mineral metabolism and vascular calcification have shed light on the systemic nature of the disorder. Central to the assessment of disturbances in the bone and mineral metabolism is the ability to assess the bone disease accurately by noninvasive means. Recent emphasis is on the requirement to begin the therapy early in the course of CKD. Guidelines on a 'step care' approach to the detection and management of alterations in calcium, phosphorus and parathyroid hormone metabolism in various stages of CKD are now available. Although constant improvements in the technicalities of the parathyroid hormone assays have improved the diagnostic capability, controversies regarding this aspect still exist. Noncalcium, nonaluminum-based phosphate binders hold promise for the future developments in the management of calcium-phosphate metabolism. Further research and progress in this area continue to evaluate the appropriate interventions to address both the skeletal and extraskeletal consequences targeted toward improving patient outcomes.


Keywords: Calcium-phosphate metabolism, chronic kidney disease, mineral and bone and disorder, renal osteodystrophy


How to cite this article:
Narula A S, Jairam A, Baliga K V, Singh K J. Pathogenesis and management of renal osteodystrophy. Indian J Nephrol 2007;17:150-9

How to cite this URL:
Narula A S, Jairam A, Baliga K V, Singh K J. Pathogenesis and management of renal osteodystrophy. Indian J Nephrol [serial online] 2007 [cited 2017 Apr 28];17:150-9. Available from: http://www.indianjnephrol.org/text.asp?2007/17/4/150/39168



  Introduction Top


Renal osteodystrophy is a common complication of chronic kidney disease (CKD) and is the part of a broad spectrum of disorders of mineral metabolism that occurs in this clinical setting. It occurs early in the course of CKD and progresses as the kidney function deteriorates. [1] This disorder should be considered with regard to not only the bone itself but also the disturbed mineral metabolism and calcification at multiple extraskeletal sites, including the vasculature. [2] The significance of the contribution of cardiovascular calcification and the associated changes in the arterial compliance to cardiovascular mortality has been recognized recently. [3],[4]

The term CKD-Mineral and Bone Disorder (CKD-MBD) has been recommended to be used to describe a broader clinical syndrome that develops as a systemic disorder of mineral and bone metabolism in CKD. The manifestations include one or more of the following: (1) abnormalities of calcium, phosphorous, parathyroid hormone (PTH) or vitamin D metabolism; (2) abnormalities in bone turnover, mineralization, volume, linear growth or strength; and (3) vascular or other soft tissue calcification.

The term renal osteodystrophy should be used exclusively to define alterations in the bone morphology associated with CKD. [5],[6] This is a single measure of the skeletal component of the systemic disorder of CKD-MBD that is quantifiable by histomorphometry of bone biopsy. The abnormalities of the bone in the setting of CKD may manifest as (1) high turnover bone disease, (2) adynamic bone disease, (3) osteomalacia and (4) mixed renal osteodystrophy.


  Physiology of Bone Remodeling Top


Bone is a dynamic tissue that is remodeled constantly throughout the life. Remodeling of the bone is under the control of two kinds of cells viz. osteoblasts and osteoclasts. [7] The process of remodeling begins by migration of osteoclasts, followed by resorption of a packet of bone by these cells. This is followed by a reversal phase characterized by the apoptosis of the osteoclasts and a final phase of bone formation by newly formed osteoblasts. The critical initial step in this process-the development of osteoclasts-is under the control of preosteoblastic/stromal cells; this ensures that the bone resorption and formation processes will be tightly coupled, allowing a wave of bone formation to follow each cycle of bone resorption thus maintaining skeletal integrity. [8] In adults, as much as 18% of the total bone calcium is removed and deposited every year. The extracellular component of the bone consists of an organic matrix and an inorganic reservoir of largely calcium and phosphorous. The organic matrix of the bone is produced by osteoblasts and mainly consists of type 1 collagen, which is involved in the formation of new bone. [9] The osteoblasts also produce several noncollagenous proteins such as osteocalcin and alkaline phosphatase, which are increased in high-turnover bone conditions. The factors implicated in the growth and differentiation of osteoblasts include interleukin 1, interleukin 6, tumor necrosis factor-α, transforming growth factor, fibroblast growth factor, bone morphogenic proteins (BMP), insulin-like growth factor (IGF) and IGF-binding protein. [9] These factors function in an autocrine manner and may also serve as the mediators of stimulation by parathyroid hormone. Other systemic processes that affect the skeleton include accumulation of β2 microglobulin and steroid-induced or post menopausal osteoporosis.

In normal subjects, PTH and vitamin D are important factors that affect bone dynamics. Receptors for PTH are found on preosteoblasts, osteoblasts and osteocytes. PTH stimulates cell proliferation, thereby increasing the number of osteocytes. Osteoclasts do not contain PTH receptors. Instead, preosteoblasts and osteoblasts signal the osteoclasts to fuse and form mature osteoclasts. [10] Two osteoblast surface proteins, macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B ligand (RANKL) are essential for stimulating osteoclastogenesis. RANKL, expressed on the surface of preosteoblastic/stromal cells, binds to RANK on the osteoclastic precursor cells. [11],[12] The binding of RANKL to its receptor can be blocked by osteoprotegrin (OPG), another member of the tumor necrosis factor (TNF) receptor family secreted by the cells of osteoblastic lineage. [Figure - 1] summarizes the process of bone remodeling and the role of the OPG/RANKL/RANK system. [8] PTH decreases the synthesis and secretion of OPG from these cells. Thus PTH serves to increase resorption by increasing RANK and decreasing OPG locally in the bone. [13] The net effect of PTH varies from one part of the bone to another. The variation in the rate of osteoclastic resorption determines the net effect of PTH on the bone. Understanding the underlying bone remodeling mechanisms in renal osteodystrophy has led to the evaluation of osteocalcin, bone alkaline phosphatase isoenzyme (BALP), procollagen, tartrate-resistant acid phosphatase (TRAP), C-terminal cross-linked peptide of collagen type 1 (ICTP) and deoxypyridinoline (DPD) as novel non-invasive markers of renal osteodystrophy. [14],[15]

The major role of 1 alpha 25, dihydroxy vitamin D3 [1,25 (OH) 2 D3] in the bone is to provide the appropriate microenvironment for bone mineralization through the stimulation of the intestinal absorption of calcium and phosphate. [16] Calcitonin may also play a role, but is a weak and transient inhibitor of bone resorption. [17] Other hormones such as thyroxin and adrenal corticoids have a permissive effect and may lead to skeletal disorders when deficient or in excess. They are not thought to play a major role in renal bone disease. Amongst the minerals, the deficiency of calcium, phosphate and bicarbonate may inhibit bone formation and enhance resorption.


  Pathogenesis of High-turnover Bone Disease Top


This is the predominant bone lesion in patients with chronic kidney disease. The lesions begin early in CKD and progress with the deterioration of disease. Many factors lead to the overactivity of the parathyroid gland. [18],[19] These include retention of phosphates, hypocalcemia, decrease in calcitriol level, skeletal resistance, intrinsic alteration within the parathyroid gland and increased parathyroid growth. All these factors are closely interrelated and one or more may predominate at different times throughout the course of the disease.

For many years it was thought Barker's 'Trade Off Hypothesis', adequately explained the PTH changes in renal failure. [20] According to this theory as renal failure advances the level of serum phosphates increase; this lowers the serum calcium levels, which stimulates PTH secretion. The latter normalizes serum calcium levels by acting on the bone and brings serum phosphorus levels towards normal by promoting phosphate excretion. Thus, a new steady state is achieved, but at the expense of a higher level of PTH. [21] Although many clinical and experimental data support this theory, many patients did not follow this pattern. As a result, several experiments were conducted that support many other mechanisms. Retention of phosphates and declining renal function suppress the synthesis of 1,25-dihydroxy vitamin D3. Experimental evidence in patients with moderate renal failure demonstrates that serum 1,25-dihydroxy vitamin D3 levels decline before serum calcium decreases, and this decrease correlates inversely with the increase in the PTH levels. The demonstration that intravenous calcitriol suppresses PTH independent of its effect on serum calcium level, appears to provide the proof that calcitriol is a direct inhibitor of PTH secretion. [22]

Some workers have shown that there is a decrease in the calcium-sensing receptors, a decrease in the vitamin D receptors and a higher set point for suppression of PTH. [23],[24] All these mechanisms result in increased parathyroid hormone secretion. Hyperphosphatemia may have a direct stimulatory effect on parathyroid metabolism. The stimulatory effect has been attributed to enhanced parathyroid cell proliferation. These effects have been demonstrated without a change in the serum calcium level and decrease in 1,25-dihydroxy vitamin D3. [25],[26] This is a posttranscriptional effect within the cell. [27] Additional investigations have demonstrated that high extracellular phosphate concentration reduces the production of arachidonic acid by the parathyroid tissue, an effect that is associated with increased PTH. [28]


  Pathogenesis of Low-turnover Bone Disease Top


Low-turnover bone disease is commonly observed in dialysis patients, but has been described in some cases even before dialysis. Adynamic bone disease is associated with the oversuppression of parathyroid gland activity due to high calcium intake (from diet, dialysate or calcium-containing phosphorus binders) and/or administration of vitamin D analogs in excess, such as 1,25-dihydroxyvitamin D 3 (calcitriol), 25-norvitamin D 2 (paricalcitol) or 1α-hydroxyvitamin D 2 (doxercalciferol), resulting in oversuppression of the parathyroid gland function. [29],[30] Whether this would also follow the use of cinacalcet (a calcimimetic agent for the treatment of secondary hyperparathyroidism in patients with CKD) is unclear because of limited experience with this drug. [31] Patients with adynamic bone disease have lower blood concentrations of PTH that may fall below the recommended target range (intact PTH [iPTH] 150-300 pg/ml), resulting in a bone turnover rate that is below normal. In these circumstances, the bone may not take up calcium for incorporation into new bone and any excess calcium may predispose to calcification in soft tissues. [31] Currently in the United States, approximately 25% of patients undergoing dialysis have a PTH concentration above the target range (high-turnover disease), approximately 25% have a PTH concentration within the target range and 50% have a PTH concentration below the target range (adynamic bone disease). [32] Age may also be a factor because many elderly patients may have low bone turnover due to postmenopausal state or associated systemic disease. Other complications of uremia can lead to a decrease in bone formation and increase in the circulating concentrations of osteoprotegrin, N-terminally truncated PTH fragments, are undefined uremic toxins, acidosis, decreased expression of PTH receptors, alteration in the concentration of growth factors such as bone morphogenic protein-7 and general malnutrition. [33]

Osteomalacia may develop after the long-term use of aluminum-based phosphorus-binding agents. [34] Under these circumstances, aluminum accumulates in the mineralization region and prevents osteoid mineralization thus leading to aluminum-related bone disease. The incidence of this entity has markedly decreased after discontinuation of the practice of using aluminium-based phosphate binders. [6]


  Vascular Calcification Top


It was initially thought that a deranged calcium and phosphate metabolism resulted in a passive deposition of calcium in the vasculature. Recent studies have demonstrated the effect of repeatedly high phosphate levels on the osteogenic markers and phenotypic expression of vascular smooth muscle cells. [35] Human smooth muscle cells are pluripotent stem cells. Under the influence of uremia and hyperphosphatemia, the smooth muscle gene expression is downregulated in preference for osteoblastic differentiation. The promoters of vascular calcification-like bone morphogenic protein-4 (BMP-4) and osteopontin expression are increased. Low levels of inhibitors of vascular calcification-like 2-Herman Schmid glycoprotein/fetuin-A and matrix-GLA protein have been demonstrated in uremic patients. Hypercalcemia precipitated by the indiscriminate use of calcium-containing phosphate binders and vitamin D analogs coupled with hyperphosphatemia further encourages vascular calcification. [36],[37]


  Issues in PTH Estimation Top


Bone biopsy-an invasive diagnostic procedure-remains the gold standard for the diagnosis of renal bone disease. PTH levels have been used for years as a noninvasive biochemical method to classify and monitor the renal bone disease. [38] With the advent of two-site immunometric technology, assays without interference from carboxy-terminal fragments have been developed. It was thought that the entire PTH molecule (1-84 amino acid) was being estimated and thus they were called 'intact PTH' (iPTH) assays. The CKD guidelines were formulated based on these iPTH assays. [39] However, it was realized that amino-terminally truncated PTH fragments such as PTH (7-84) interfere with the estimation in the iPTH assays. [40],[41] The second generation radioimmunometric immunoassays that do not detect other PTH fragments lacking one or more amino acids from the amino terminal are available. These detect the entire PTH molecule (1-84) and are also called the biointact PTH [biPTH] assay. [42] The results of biPTH are approximately 50% of that for iPTH assays; hence, a knowledge of the methodology of the assays used to determine target values is important. In a study comparing the biPTH and I-PTH assays in predicting bone morphology, both assays were good in differentiating between the high- and low-turnover bone diseases, although biPTH assay appeared to provide a marginally better discrimination. [43]


  Management of Renal Bone Disease Top


The objectives of management are to maintain blood levels of calcium and phosphorous to as close to normal as possible, to prevent or treat established hyperparathyroidism early and to prevent parathyroid hyperplasia. [1],[44] Additional aims are to prevent extraskeletal calcification and avoid the oversuppression of parathyroid secretion. Appropriate management requires a balanced diet, phosphorus binders, vitamin D analogs and calcimimetics agents. [Table - 1] presents the recommended target ranges of the intact parathyroid hormone, calcium and phosphorus concentrations and calcium-phosphorus product at the CKD stage. [1]

Central to the management of high-turnover bone disease is controlling the serum phosphate levels. Phosphate retention begins early in the course of CKD, perhaps as early as in stage 2 and participates in the development of secondary hyperparathyroidism. [45] Early in the course of CKD, circulating iPTH is a better marker for the need to begin dietary phosphate restriction than serum phosphate concentration, which remains within or close to the normal range until the GFR declines to 20-30 ml/min/1.73 m 2 (stage 4 CKD). [46]

It is recommended that dietary phosphates be restricted to 800-1000 mg/day (adjusted for dietary protein needs) when the serum phosphate concentrations are elevated to greater than 4.6 mg/dl at stages 3 and 4 of CKD and greater than 5.5 mg/dl in those with stage 5 CKD, or when the plasma concentrations of iPTH are elevated above the target range for the CKD stage. Serum phosphate concentrations should be monitored every month after the start of dietary phosphate restriction. [47]

Phosphate-binder therapy is recommended when serum phosphate concentrations are elevated despite patient compliance with dietary phosphate restriction; or when serum phosphate concentrations can be controlled only when such dietary intervention hinders the intake of other critical nutrients; or when blood PTH concentrations remain elevated after dietary phosphorus restriction, even if the serum phosphorus concentrations are not elevated. [44],[48]

Calcium-based phosphate binders are often recommended as the initial binder therapy. [49],[50] The total dosage of elemental calcium provided by the calcium-based phosphate binders should not exceed 1500 mg/day, and the total intake of elemental calcium (including dietary calcium) should not exceed 2000 mg/day. [51] Calcium-based phosphate binders should not be used in patients undergoing dialysis who are hypercalcemic, have evidence of metastatic calcification or whose plasma PTH concentrations are below 150 pg/ml.

Noncalcium-based phosphorus binders containing aluminum are recommended only for a short duration when the phosphate levels are unacceptably high. [44] The increasing concern regarding aluminum toxicity and hypercalcemia has led to the use of sevelamer and lanthanum carbonate as the therapy of choice in patients undergoing dialysis who have high serum phosphate concentrations and/or low PTH concentrations. [52],[53] The rationale for this recommendation is that these patients will usually have low-turnover bone disease and the bone will be unable to incorporate a calcium load, predisposing to extra skeletal calcification. [54] In patients undergoing dialysis and who remain hyperphosphatemic (serum phosphorus concentration > 5.5 mg/dl) despite the use of calcium-based phosphate binders or other noncalcium phosphate binders, a combination of both has been recommended. In such patients, more frequent dialysis should also be considered. The optimal timing for ingestion of phosphate binders is 10-15 min before or during a meal to maximize the contact with ingested phosphates. [1]

Extensive clinical experience is available for sevelamer hydrochloride, a nonabsorbable exchange resin, which has proved to be equivalent, although not superior, to calcium carbonate or calcium acetate in terms of its phosphate chelating capacity. [55] The present recommended dosage is 800-1600 mg with major meals to a maximum of 4800 mg per day. Sevelamer hydrochloride significantly reduces serum phosphate and calcium-phosphorus product with a potency equivalent to that observed with calcium acetate therapy, but with considerably less risk of elevation of serum calcium levels. [56],[57],[58],[59] Despite equivalent phosphorus control, sevelamer has been demonstrated to attenuate the progression of coronary calcification as compared with calcium acetate in both prevalent (Treat To Goal trial) and incident (Renagel in New Dialysis trial) hemodialysis patients. [60],[61] Sevelamer has been shown to lower lipids and uric acid levels, reduce inflammation and oxidative stress, increases serum fetuin-A levels and improves bone health. [62],[63] The fact that sevelamer therapy prevents hypercalcemia and has multiple pleiotropic effects, have been thought to contribute to the abolition of progression of vascular calcification and/or the survival benefit. A disadvantage of sevelamer hydrochloride is reduction in serum bicarbonate level. [64]

Lanthanum carbonate is an alternative nonaluminum, noncalcium phosphate binder. [65] When ingested along with food, it is well tolerated. It is poorly absorbed and does not require functioning kidneys to be removed from the body. Currently, there is no evidence for its accumulation at biologically significant levels in tissues; however, despite the large numbers of patients included in clinical trials, experience with long-term dosage is limited. Lanthanum carbonate binds phosphate effectively across the physiological pH range of the upper gastrointestinal tract and has no detrimental effect on calcium, vitamin D or parathyroid hormone metabolism. The recommended dose is 250-500 mg with meals, to a maximum of 1500 mg daily. [66] From the extensive trial data, it appears that lanthanum carbonate is an effective and practical phosphate binder.

Serum concentrations of 25(OH) D are the measure of storage of vitamin D in the body. In healthy individuals above 60 years of age, 25(OH) D concentrations below the normal limit of 15 ng/ml and also low-to-normal concentrations of 16-32 ng/ml are associated with increased PTH concentrations, reduced bone mineral density and increased rates of hip fracture. For several reasons, the concentrations of 25(OH) D are low in patients with stages 3-5 CKD. [67],[68],[69] Firstly, many CKD patients lead a sedentary lifestyle with reduced exposure to sunlight. Secondly, the ingestion of foods that are natural sources of vitamin D (fish, cream, milk and butter) tends to be lower than in the population with normal kidneys. Thirdly, serum 25(OH) D concentrations may be subnormal in patients with CKD because the endogenous synthesis of vitamin D 3 in the skin after identical exposure to sunlight is reduced in those with reduced GFR, in individuals above 60 years of age and in individuals with high melanin content of the skin.

The prevention and treatment of vitamin D insufficiency in patients with stages 3 and 4 CKD probably reduces the frequency and severity of secondary hyperparathyroidism. In stages 3 and 4 CKD, if plasma iPTH is above the target range for the stage of CKD, serum 25-hydroxyvitamin D concentration should be measured and if below 30 ng/ml, supplementation with vitamin D 2 (ergocalciferol) should be started. [1] Ergocalciferol therapy should be integrated with the serum calcium and phosphate concentrations. Serum concentrations of corrected total calcium and phosphate should be measured at least every 3 months. If the serum concentration of corrected total calcium exceeds 10.2 mg/dl, ergocalciferol therapy should be discontinued. If the serum phosphate concentration exceeds 4.6 mg/dl, phosphate binder should be added or dosage increased. If hyperphosphatemia persists, vitamin D therapy should be discontinued until plasma concentrations normalize. Once patients are replete with vitamin D, supplementation with a vitamin D-containing multivitamin preparation should be continued, with annual reassessment of serum 25(OH) D concentrations and the continued assessment of corrected total calcium and phosphorus concentrations every 3 months.

In patients with CKD Stages 3 and 4, therapy with an active oral vitamin D sterol (calcitriol, alfacalcidol or doxercalciferol) is indicated when serum levels of 25(OH)-vitamin D are >30 ng/mL and plasma levels of intact PTH are above the target range for the CKD stage. [1] Treatment with an active vitamin D sterol should be undertaken only in patients with serum levels of corrected total calcium <9.5 mg/dL and serum phosphorus <4.6 mg/dL.

During therapy with vitamin D sterols, serum levels of calcium and phosphorus should be monitored at least every month after the initiation of therapy for the first 3 months, then every 3 months thereafter. Plasma PTH levels should be measured at least every month for 6 months and every 3 months thereafter. In stage 5, CKD, therapy with an active vitamin D sterol (calcitriol, alfacalcidol, paricalcitol or doxercalciferol) should be provided if the plasma concentration of iPTH is above 300 pg/ml. [1] When therapy with vitamin D sterols is begun or the dosage is increased, serum calcium and phosphorus concentrations should be monitored at least every 2 weeks for 1 month and monthly thereafter. Plasma PTH should be measured monthly for at least 3 months and then every 3 months once the target concentrations of PTH is achieved. [1]

The native hormone calcitriol is available both orally and intravenously. Intermittent, intravenous administration (known as pulse dosing) of calcitriol is more effective than daily oral calcitriol in lowering plasma PTH concentrations. [70],[71] Other vitamin D preparations include vitamin D prohormones such as 1α hydroxyvitamin D3, 1α hydroxyvitamin D2 (doxercalciferol); vitamin D analogues such as 19-nor-1, 25-dihydroxyvitamin D2 (paricalcitol), 22-oxacacitriol and 26,27-hexa fluorocalcitriol and synthetic vitamin D such as dihydrotachysterol. In patients with corrected serum calcium and/or phosphate concentrations above the target range, a trial of alternative vitamin D analogs, such as paricalcitol or doxercalciferol may be warranted. [72]

According to the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines, [1] patients who develop hypercalcemia (corrected calcium >9.5 mg/dL) or whose iPTH level falls below the target range should temporarily discontinue the use of vitamin D and resume treatment at half the dose once the levels return to the target range. Those who develop hyperphosphatemia (phosphorus >4.6 mg/dL) should temporarily discontinue vitamin D and initiate a phosphate binder, then resume vitamin D therapy at the same dose once the levels return to the target range.

However, newer data suggest that discontinuation of vitamin D may actually be associated with an increase in the risk of death, even in patients with hypercalcemia or hyperphosphatemia, or those in whom the iPTH level is below the target range. [73],[74] In a study conducted by Teng and colleagues, [73] increasing quintiles of calcium, phosphorus and iPTH levels were associated with increases in the risk of death. However, within each quintile, patients treated with injectable vitamin D had a considerably lower risk of death than those who did not receive vitamin D therapy. Further analyses revealed that in patients with a baseline serum calcium level above 10.2 mg/dL, a serum phosphorus level above 6.0 mg/dL or a serum iPTH level below 150 pg/mL, the survival advantage associated with vitamin D therapy was 24% (hazard ratio [HR], 0.76; 95% CI, 0.54-1.08), 19% (HR, 0.81; 95% CI, 0.74-0.89) and 21% (HR, 0.79; 95% CI, 0.74-0.85), respectively. Thus, based on these data, it can be speculated that the same survival benefit holds true in patients in whom the calcium-phosphorus product exceeds the current upper limit of the K/DOQI range (i.e., 55 mg 2 /dL 2 ). These results demonstrate a definitive survival benefit associated with vitamin D therapy, even in patients in whom the calcium, phosphorus and iPTH levels fall beyond their respective K/DOQI target ranges.

Administration of vitamin D analogs can stimulate vitamin D receptors in many tissues. A major adverse effect of vitamin D treatment is an increased absorption of calcium and phosphorus in the intestine, due to the stimulation of vitamin D receptors in the gastrointestinal system. As a result, hypercalcemia may appear, hyperphosphatemia may be aggravated and both may lead to the complications associated with elevations in the calcium-phosphorus product. Acute hypercalcemia is also a potential complication, particularly when corrected serum calcium concentrations exceed 10.5 mg/dl. The newer vitamin D 2 analogs, paricalcitol and doxercalciferol, may be less likely to cause hypercalcemia. [75],[76]

Treatment with vitamin D sterols can markedly lower plasma concentrations of iPTH and lead to adynamic bone disease. [77] Adynamic bone disease is a nearly universal disorder occurring when iPTH concentrations are below 65 pg/ml. Mild hyperparathyroidism may be preferable to adynamic bone disease because of the loss of the capacity of bone buffering for the added extracellular calcium, which accounts for the increased risk of hypercalcemia in patients with adynamic bone disease. [78] Thus, serum calcium and phosphorus concentrations and plasma PTH concentrations should be monitored during vitamin D therapy, and accordingly this therapy should be adjusted.

The calcimimetics such as cinacalcet provides a novel method of PTH suppression, i.e., by activating the calcium-sensing receptors in the parathyroid tissue. This form of therapy is particularly useful for patients in whom the serum calcium and phosphorous levels are at or slightly above the upper limits of the normal values, and in whom the use of vitamin D sterols might result in certain complications. [79],[80]

It has been proposed that parathyroidectomy should be considered in such patients if the mass of parathyroid tissue estimated by imaging procedures exceeds approximately 0.5-1 g, [81],[82] if hypercalcemia or hyperphosphatemia is resistant to conservative management [83],[84] or when biomechanical concerns arise (e.g., fractures, tendon rupture, etc.) and for severe pruritus refractory to medical management in a patient with massively elevated PTH concentrations. Unfortunately, only a minority of patients with pruritus responds to parathyroid surgery. Calciphylaxis in the context of increased intact PTH is a definite indication for parathyroidectomy. [1] The exclusion of aluminium bone disease and other bone pathologies is essential before parathyroidectomy. This may necessitate a bone biopsy and/or a desferrioxamine test. When the aluminium stress is high, the postoperative risk of symptomatic low-turnover aluminium bone disease is particularly high. [85] If present, aluminium intoxication should be treated by desferrioxamine before parathyroidectomy. Alternatively, such patients have been successfully managed by percutaneous ethanol injection therapy (PEIT). [86],[87] However, 20% of patients after PEIT are required to undergo parathyroidectomy. [88]

The suggested approach to high-turnover bone disease is depicted in [Table - 2]. [6]

Increasing bone turnover through an increase in PTH has been attempted in patients with adynamic bone disease. Lowering the doses of calcium-based phosphate binders and vitamin D or entirely eliminating such therapy can best accomplish this. The lowering of dialysate calcium (1.0-2.0 mEq/L) has also been suggested as a possible approach. [1],[89] Manipulation of the calcium receptor with calcilytics (which stimulate PTH release) may also become important therapeutic agents. [90]

Management of vascular calcification is a challenging area that still remains controversial. Most strategies to decrease vascular calcification have concentrated on the control of serum phosphorus. However, few studies have demonstrated the benefits of reducing serum phosphorus on vascular calcifications and mortality. A recent clinical trial showed that compared with calcium carbonate, sevelamer, at 6 and 12 months, reduced the progression of both coronary and aortic calcifications, measured by electron beam computed tomography. [60] This effect was possibly due to the pleiotropic effects of sevelamer because both treatments were effective in controlling hyperphosphatemia.

Although it is widely known that a high dosage of vitamin D metabolites favors the onset and progression of vascular calcifications and its complications, several recent studies demonstrated a long-term beneficial effect of vitamin D metabolites on proliferative, cardiovascular and immune disorders and also on survival rates. [73] Moreover, some differential effects of the vitamin D metabolites and analogues were demonstrated. [91],[92] In addition, clinical and epidemiologic studies have already shown in various populations a negative relationship between serum calcitriol and/or calcidiol levels and cardiovascular events or vascular calcifications, suggesting that maintaining high-normal serum values of these two metabolites may have positive implications in clinical outcomes. [93]

In animal studies, calcimimetics have proven to be beneficial in decreasing the vascular calcifications. [94] Bisphosphonates may have a potential future role in the management of vascular calcifications. [95] A recent report in a group of hemodialysis patients demonstrated that etidronate reduced and even reversed the progression of coronary artery calcifications after 6 months of treatment. [96] Animal studies have suggested that OPG might have a role in the future as a therapeutic agent. [97]

Despite new strategies that may improve the management of vascular diseases and have a positive impact on the high prevalence of vascular calcifications, our best available tools are related to the best possible control of the bone metabolic and inflammatory parameters. Recent preliminary data from the Control de la Osteodistolia Renal en Sudamιrica (CORES) study showing that a sustained control (at least 2 years) of bone metabolic parameters according to K/DOQI guidelines may have a positive impact on morbidity and mortality are encouraging. [98]

The mineral and bone metabolisms are complex abnormalities that cause morbidity and decreased quality of life in patients with CKD. In order to enhance communication and facilitate research, a more precise system of classification and terminologies has been proposed. New data continue to add to our description of the process related to the ideal biomarkers, imaging techniques and therapeutic protocols. We hope that, as a result of these advances, the outcomes of the patients with CKD can be improved.

 
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