Bone disease renal osteodystrophy

Secondary hyperparathyroidism Increased secretion of parathyroid hormone from the parathyroid glands caused by hyperphosphatemia, hypocalcemia, and vitamin D deficiency that result from decreased kidney function. It can lead to bone disease (renal osteodystrophy). 

It is indicated in osteoporosis, hypoparathyroidism, hyperparathyroidism (with bone disease), renal osteodystrophy, nutritional and malabsorptive rickets, hypophosphataemic vitamin D resistant rickets and osteomalacia. 

Patients with end-stage renal disease hyperphosphatemia ineffectively filter excess phosphate that enters the body in the normal diet.278 Elevated phosphate produces the bone disorder renal osteodystrophy. Skeletal deformity may occur, possibly associated with cardiovascular disease. Calcium deposits may further build up around the body and in blood vessels creating further health risks. The use of lanthanum carbonate is being promoted as an alternative to aluminum-based therapies.279,280 Systemic absorption, and cost have produced a clinical candidate, Fosrenol (AnorMED), an intriguing use of a lanthanide compound in therapy. 

Metabolic bone diseases result from a partial uncoupling or imbalance between bone resorption and formation. Decreased bone mass, or osteopenia, is more common than abnormal increases of bone mass. The most prevalent metabolic bone diseases are osteoporosis, osteomalacia and rickets, and renal osteodystrophy. Osteoporosis, the most prevalent metabolic bone disease in developed countries, is characterized by loss of bone mass, microarchitectural deterioration of bone tissue, and increased risk of fracture. Rickets and osteomalacia, which are more common in the less-developed countries, are characterized by defective mineralization of bone matrix. Renal osteodystrophy is a complex condition that develops in response to abnormalities of the endocrine and excretory functions of the kidneys. These three metabolic bone diseases and Paget s disease, a localized bone disease, are discussed below followed by laboratory markers of bone metabolism. 

In the treatment of diseases where the metaboUtes are not being deUvered to the system, synthetic metaboUtes or active analogues have been successfully adrninistered. Vitamin metaboUtes have been successfully used for treatment of milk fever ia catde, turkey leg weakness, plaque psoriasis, and osteoporosis and renal osteodystrophy ia humans. Many of these clinical studies are outlined ia References 6, 16, 40, 51, and 141. The vitamin D receptor complex is a member of the gene superfamily of transcriptional activators, and 1,25 dihydroxy vitamin D is thus supportive of selective cell differentiation. In addition to mineral homeostasis mediated ia the iatestiae, kidney, and bone, the metaboUte acts on the immune system, P-ceUs of the pancreas (iasulin secretion), cerebellum, and hypothalamus. 

Renal osteodystrophy Altered bone turnover that results from sustained metabolic conditions that occur in chronic kidney disease, including secondary hyperparathyroidism, hyperphosphatemia, hypocalcemia, and vitamin D deficiency. 

Calcium-phosphorus balance is mediated through a complex interplay of hormones and their effects on bone, GI tract, kidney, and parathyroid gland. As kidney disease progresses, renal activation of vitamin D is impaired, which reduces gut absorption of calcium. Low blood calcium concentration stimulates secretion of parathyroid hormone (PTH). As renal function declines, serum calcium balance can be maintained only at the expense of increased bone resorption, ultimately resulting in renal osteodystrophy (ROD) (Fig. 76-7). 

Renal osteodystrophy is a complex disorder with several pathogenic factors. Histological evidence of bone disease is common in early renal failure and deficits in calcitriol synthesis seems to be an important factor in the pathogenesis of secondary hyperparathyroidism in early CRF. The most common component is osteitis fibrosa manifested as subperiosteal resorption of bone. This is due to decreased excretion as well as increased secretion of parathyroid hormone. In CRF small increments of serum phosphorus cause small decreases in serum calcium. 

Patients with chronic renal failure develop hyperphosphatemia, hypocalcemia, secondary hyperparathyroidism, and severe metabolic bone disease. The secondary hyperparathyroidism is thought to be due to hyperphosphatemia and decreased 1, 25-(OH)2 formation. Oral or intravenous l,25-(OH)2D3 (calcitriol) therapy along with oral phosphate-binding agents and calcium supplementation is effective in reducing the effects of renal osteodystrophy. 

In mild forms of malabsorption, vitamin D (25,000-50,000 units three times per week) should suffice to raise serum levels of 25(OH)D into the normal range. Many patients with severe disease do not respond to vitamin D. Clinical experience with the other metabolites is limited, but both calcitriol and calcifediol have been used successfully in doses similar to those recommended for treatment of renal osteodystrophy. Theoretically, calcifediol should be the drug of choice under these conditions, because no impairment of the renal metabolism of 25(OH)D to l,25(OH)2D and 24,25(OH)2D exists in these patients. Both calcitriol and 24,25(OH)2D may be of importance in reversing the bone disease. However, calcifediol is no longer available. 

Dihydrotachysterol, an analog of l,25(OH)2D, is also available for clinical use, though it is used much less frequently than calcitriol. Dihydrotachysterol appears to be as effective as calcitriol, differing principally in its time course of action calcitriol increases serum calcium in 1-2 days, whereas dihydrotachysterol requires 1-2 weeks. For an equipotent dose (0.2 mg dihydrotachy-sterol versus 0.5 ug calcitriol), dihydrotachysterol costs about one fourth as much as calcitriol. A disadvantage of dihydrotachysterol is the inability to measure it in serum. Neither dihydrotachysterol nor calcitriol corrects the osteomalacic component of renal osteodystrophy in the majority of patients, and neither should be used in patients with hypercalcemia, especially if the bone disease is primarily osteomalacic. 

A number of gastrointestinal and hepatic diseases result in disordered calcium and phosphate homeostasis that ultimately leads to bone disease. The bones in such patients show a combination of osteoporosis and osteomalacia. Osteitis fibrosa does not occur (as it does in renal osteodystrophy). The common features that appear to be important in this group of diseases are malabsorption of calcium and vitamin D. Liver disease may, in addition, reduce the production of 25(OH)D from vitamin D, though the importance of this in all but patients with terminal liver failure remains in dispute. The malabsorption of vitamin D is probably not limited to exogenous vitamin D. The liver secretes into bile a substantial number of vitamin D metabolites and conjugates that are reabsorbed in (presumably) the distal jejunum and ileum. Interference with this process could deplete the body of endogenous vitamin D metabolites as well as limit absorption of dietary vitamin D. 

Vitamin D-binding protein and its associated vitamin are lost in nephrotic urine. Biochemical abnormalities in nephrotic patients (children and adults) include hypocalcemia, both total (protein-bound) and ionized hypocalciuria, reduced intestinal calcium absorption and negative calcium balance reduced plasma 25-hydroxycholecalciferol and 24,25-dihydroxycholecalciferol and, surprisingly, also 1,25-dihydroxycholecalciferol and blunted response to parathormon (PTH) administration and increased PTH levels. Clinically, both osteomalacia and hyperparathyroidism have been described in nephrotic patients, more commonly in children than in adults, but bone biopsies are commonly normal, and clinically significant bone disease is very rare in nephrotic subjects. There is, however, evidence that patients with renal failure accompanied by nephrotic range proteinuria may be particularly prone to develop renal osteodystrophy. 

Hyperparathyroidism and aluminium hydroxide lead to aluminium-related bone disease however, total parathyroidectomy does not lead to failure of aluminium mobilization after renal transplantation. This man had satisfactory graft function, and the aluminium excretion that was achieved by deferoxamine suggests that the renal transplant was not the limiting factor for the mobihzation of aluminium. The most likely explanation was that he developed adynamic bone through a combination of vitamin D deficiency, hypoparathyroidism, and aluminium deposition. Vitamin D supplementation failed to prevent the osteodystrophy on its own. When aluminium chelation therapy was used, bone healing occurred and his symptoms improved. 

The distribution of the element is similar to that of calcium which means that 99% of the body burden is deposited in bone [44]. Within the dialysis population, bone strontium levels were found to be significantly higher in subjects with osteomalacia as compared to this presenting the other types of renal osteodystrophy [45]. A causal, dose-dependent role of strontium in the development of this bone disease has been established in a chronic renal failure ratmodel [46,47]. Moreover the bone osteomalacic lesions were found to be reversible after withdrawal of strontium [9,48]. 

Intermediate concentrations are seen in low-turnover adynamic (aplastic) disease and early osteitis fibrosa. Considerable overlap in intact PTH concentrations is apparent among the various forms of renal osteodystrophy. In dialysis patients, cut-points ( decision levels ) of less than 100 or 150 pg/mL and greater than 250 to 300 pg/mL have been suggested for distinguishing patients with low-turnover and high-turnover bone disease, respectively. A reasonable therapeutic goal for intact PTH (first generation) concentrations is two to four times the upper limit of the reference interval to prevent parathyroid-suppressed, adynamic, and hyperparathyroid bone diseases. ... 

Renal osteodystrophy includes all of the disorders of bone and mineral metabolism associated with chronic renal failure. The renal bone diseases include both... 

BAP is increased in metabolic bone diseases, including osteoporosis, osteomalacia and rickets, hyperparathyroidism, renal osteodystrophy, and thyrotoxicosis, and in individuals with acromegaly, bony metastases, glucocorticoid excess, Paget s disease, and other disorders with increased bone formation." ... 

Renal osteodystrophy (ROD)—The condition resulting from sustained metabolic changes that occur with chronic kidney disease including secondary hyperparathyroidism, hyperphosphatemia, hypocalcemia, and vitamin D deficiency. The skeletal complications associated with ROD include osteitis fibrosa cystica (high bone turnover disease), osteomalacia (low bone turnover disease), adynamic bone disease, and mixed bone disorders. 

Hyperphosphatemia occurs commonly in chronic renal failure. The increased phosphate level direcdy stimulates PTH secretion and also has secondary effects due to the reduction in serum Cd . Because renal function is impaired, the increased PTH is unable to increase phosphate excretion sufficiently to avoid ongoing phosphate retention. The chronic secondary hyperparathyroidism may result in a bone disease called renal osteodystrophy. 

With advanced age, there is an increased impairment of renal function which has been shown to correlate with elevated PTH levels and radiologic bone disease (11). When the impairment of function reaches the renal failure stage, 2HPT has been found in 80-94X of patients (M,60). While some patients are asymptomatic, osteodystrophy is often manifested as spontaneous fractures (femoral neck, vertebrae) or bone and joint pains (59). Chronic hemodialysis may cause an exacerbation of the 2HPT and increase the risk of bone disease (61,62). 

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