Chapter 20. Renal Osteodystrophy

The kidneys play a crucial role in the regulation of mineral metabolism by serving both excretory and endocrine functions. Each of these components becomes compromised as renal function declines. In the broadest sense, the term renal osteodystrophy encompasses all of the disorders of bone and mineral metabolism that are associated with chronic kidney disease (CKD). Often, however, the term is used more narrowly to describe the various skeletal disorders and their histologic manifestations among patients with renal dysfunction.

Disturbances in calcium, phosphorus, and vitamin D metabolism, alterations in the regulation of parathyroid hormone (PTH) synthesis and secretion, and factors that lead to the development of parathyroid gland hyperplasia are key components in the pathogenesis of renal bone disease. Additional pathogenic factors include systemic acidosis, aluminum retention, and the accumulation of β2-microglobulin (β2M) in bone and joints. The skeletal manifestations of renal bone disease in individual patients are determined ultimately by the interplay among one or more of these causative factors.

• Disorder of bone and mineral metabolism associated with chronic renal disease.
• Skeletal disorders associated with renal dysfunction.
• Disturbances in calcium, phosphorus, and vitamin D metabolism.
• Parathyroid gland hyperplasia.
• Systemic acidosis, aluminum retention, accumulation of β2M in bone and joints.

The renal bone diseases represent a spectrum of skeletal disorders ranging from high-turnover lesions arising predominantly from excess PTH secretion to low-turnover lesions of diverse etiology that are typically associated with normal or reduced plasma PTH levels (Figure 20–1). Transitions among histologic subtypes are determined by one or more dominant pathogenic factors. Such changes can be documented by bone biopsy and quantitative bone histology, which represent the definitive method for the diagnosis of renal osteodystrophy. Because plasma PTH levels are a major determinant of bone formation and turnover among patients with CKD, alterations in parathyroid gland function play a key role in the pathogenesis and evolution of renal osteodystrophy. Other factors, however, including diabetes, age-related bone loss, postmenopausal osteoporosis, gender, and race have been recognized increasingly as potentially important additional modifiers of skeletal metabolism and bone turnover among patients undergoing dialysis regularly. Such considerations are particularly relevant given the evolving demographics of the dialysis population in the United States, which is composed increasingly of persons older than 65 years of age and those with diabetes.

High-Turnover Renal Bone Disease

Secondary Hyperparathyroidism

Several factors contribute to sustained increases in plasma PTH levels and, ultimately, to the development of high-turnover skeletal lesions in patients with chronic renal failure. Among these are hypocalcemia, impaired renal calcitriol, or 1,25-dihydroxyvitamin D, production, skeletal resistance to the calcemic actions of PTH, alterations in the regulation of prepro-PTH gene transcription, reductions in vitamin D receptor (VDR) and calcium-sensing receptor (CaSR) expression in the parathyroids, and hyperphosphatemia due to diminished renal phosphorus excretion.

Because blood ionized calcium levels represent the most immediate stimulus for PTH secretion, disturbances that lead to hypocalcemia in patients with kidney disease promote excess PTH secretion. Renal 1,25-dihydroxyvitamin D production serves to maintain serum calcium levels by promoting active intestinal calcium absorption, by facilitating calcium release from bone, and by enhancing renal tubular calcium reabsorption. Serum calcitriol levels fall progressively, however, as renal function declines with wide-ranging effects on mineral homeostasis. Although serum 1,25-dihydroxyvitamin D levels vary considerably at any given level of renal function, the proportion of patients with subnormal values increases as renal failure worsens. Such changes account, at least in part, for impaired intestinal calcium absorption and for moderate reductions in serum calcium concentration in many patients with moderate to advanced renal failure. Diminished VDR expression in intestinal epithelial cells may contribute to this disturbance.

Skeletal resistance to the calcemic actions of PTH further compromises the ability to maintain serum calcium levels in those with advanced renal disease. As a result, higher serum PTH levels are required to elicit equivalent biologic responses in patients with chronic renal failure. Abnormalities in vitamin D metabolism and alterations in VDR expression may contribute to this abnormality.

Because calcitriol is a potent inhibitor of cell proliferation, disturbances in renal 1,25-dihydroxyvitamin production and/or reductions in VDR expression have been thought traditionally to contribute to the development of parathyroid hyperplasia in CKD. Vitamin D receptor expression is markedly reduced in parathyroid tissues that exhibit a nodular pattern of tissue hyperplasia, whereas decreased reductions occur in glands with diffuse chief-cell hyperplasia. Moreover, the extent of glandular enlargement is generally greater in the nodular form of parathyroid hyperplasia.

The development and progression of parathyroid gland hyperplasia are a critically important components of renal secondary hyperparathyroidism. Once established, parathyroid enlargement is difficult to reverse because the rate of apoptosis in parathyroid tissue is quite low and the half-life of parathyroid cells has been estimated to exceed 30 years. Clinical assessments of parathyroid gland function demonstrate that differences in functional parathyroid gland size account largely for wide variations in basal plasma PTH levels among patients with advanced renal failure. The secretion of PTH from massively enlarged parathyroid glands may ultimately become uncontrolled due to the ongoing nonsuppressible component of calcium-regulated PTH release thus leading to hypercalcemia and progressive bone disease in patients with advanced CKD.

Phosphorus retention and hyperphosphatemia have been recognized for many years as important factors in the pathogenesis of secondary hyperparathyroidism. The disorder can be prevented in experimental animals with chronic renal failure when dietary phosphorus intake is reduced in proportion to glomerular filtration rate (GFR). Dietary phosphate restriction also lowers plasma PTH levels in patients with moderate renal failure.

Phosphorus retention and hyperphosphatemia appear to aggravate secondary hyperparathyroidism in several ways. Marked elevations in serum phosphorus concentration may lead to the formation of soluble complexes of calcium and phosphorus in plasma, lower blood ionized calcium concentrations, and thus stimulate PTH secretion. Phosphorus abundance impairs renal 1α-hydroxylase activity directly and reduces 1,25-dihydroxyvitamin D synthesis. Either phosphorus retention or renal failure per se may affect posttranscriptional events that influence PTH mRNA stability and hormone synthesis. Finally, phosphorus retention can aggravate parathyroid gland hyperplasia by altering the expression of factors involved in cell cycle regulation and parathyroid cell proliferation.

The skeletal manifestations of hyperparathyroidism are often more pronounced in patients with secondary as compared to those with primary hyperparathyroidism, probably because of the very high plasma PTH levels that occur in renal failure. Values are typically 5- to 10-fold above the upper limit of normal among patients with secondary hyperparathyroidism due to advanced CKD, and they may reach levels that are 20–40 times higher than normal. By contrast, plasma PTH levels in most patients with primary hyperparathyroidism are only 2- to 3-fold above the upper limit of normal.

Unlike those with advanced renal disease who are treated with dialysis, patients with moderate renal insufficiency often have overt histologic evidence of secondary hyperparathyroidism when PTH levels are only modestly elevated. The disparity in disease severity despite markedly different plasma PTH levels between patients with moderate and advanced renal failure is probably attributable to differences in skeletal resistance to the biologic actions of PTH and/or to disturbances in vitamin D metabolism.

Low-Turnover Renal Bone Disease

Adynamic bone and osteomalacia: In the past, secondary hyperparathyroidism developed almost invariably in untreated patients with progressive renal disease. More recently, however, fewer patients have markedly elevated plasma PTH levels when regular dialysis is begun. Many have bone biopsy evidence of adynamic renal osteodystrophy, which is characterized by subnormal rates of bone formation and turnover. As mentioned previously, changes in the demographics of the dialysis population may account for this change.

Adynamic renal osteodystrophy currently accounts for most cases of low-turnover bone disease in patients undergoing dialysis regularly. Osteomalacia is seen much less often. Approximately 40% of those treated with hemodialysis and more than 50% of those receiving peritoneal dialysis have plasma PTH levels that are only modestly elevated or that fall within the normal reference range. Such values are typically associated with reduced rates of bone formation and turnover without evidence of defective skeletal mineralization.

In the 1970s and 1980s, aluminum retention and bone aluminum accumulation accounted for most cases of adynamic bone and osteomalacia among patients with CKD. Two distinct patterns of aluminum exposure were described. One was due to inadequate water purification during the preparation of dialysis solutions, which led to inadvertent parenteral aluminum loading. The other was due to the long-term ingestion of aluminum-containing, phosphate-binding agents, which led to gradual aluminum loading from intestinal aluminum absorption. Bone aluminum deposition was a prominent finding both in patients with adynamic bone and in those with osteomalacia. Bone and muscle pain, proximal myopathy, and skeletal fracture were common. Bone histology improved and bone formation increased when aluminum overload was treated effectively.

Aluminum has diverse effects on bone and mineral metabolism. It inhibits the proliferation and the differentiated function of osteoblasts, reduces collagen synthesis, and suppresses PTH secretion. Accordingly, adynamic bone due to aluminum retention may arise both through direct inhibitory actions of aluminum on osteoblasts and through indirect effects on bone cell activity that are mediated by reductions in parathyroid gland function and low plasma PTH levels. Aluminum also interferes directly with skeletal mineralization to cause osteomalacia.

Risk factors for aluminum-related bone disease include previous parathyroidectomy, a history of renal transplantation and graft failure, bilateral nephrectomy, and diabetes mellitus. By promoting the formation of soluble complexes with aluminum, citrate markedly enhances intestinal aluminum absorption, and the use of citrate-containing compounds in patients with renal failure who are also ingesting aluminum-containing medications should be avoided. High plasma PTH levels appear to partially offset the adverse skeletal effects of aluminum. This may account for the somewhat greater risk of aluminum-related bone disease among diabetic patients and those who have undergone parathyroidectomy previously, conditions associated with low plasma PTH levels.

Fortunately, aluminum-related bone disease is now uncommon. Diabetes, corticosteroid therapy, and increasing age account for adynamic lesions in many patients. In this regard, the proportion of diabetic and elderly patients in the dialysis population continues to increase. Many of the histologic features of adynamic renal osteodystrophy are indistinguishable from those of osteoporosis from any of a variety of causes. The possibility of osteoporosis from causes other than renal bone disease must be considered when reductions in trabecular bone volume or cortical thinning are prominent histologic features in patients with CKD because such changes are not integral components of adynamic renal osteodystrophy.

The widespread use of large doses of oral calcium as a phosphate-binding agent and the use of large doses of active vitamin D sterols to treat secondary hyperparathyroidism may account for the increased prevalence of adynamic bone among patients receiving dialysis. Both interventions can lead to sustained reductions in plasma PTH levels. Calcitriol may also diminish osteoblastic activity directly when given in large intermittent doses to patients undergoing regular dialysis.

The long-term consequences of adynamic renal osteodystrophy, when not due to aluminum toxicity, remain uncertain. Some studies suggest that the risk of skeletal fracture may be greater among patients with relatively low plasma PTH levels, although the data are not conclusive. The prevalence and extent of arterial calcification have been reported to be greater among adult dialysis patients with adynamic skeletal lesions than in those with hyperparathyroidism. Episodes of hypercalcemia, which occur more often in those with adynamic renal osteodystrophy, may be contributory. In prepubertal children, adynamic skeletal lesions have been reported to be associated with reductions in linear growth.

For patients with osteomalacia, aluminum toxicity must be excluded if there is a history of sustained aluminum ingestion or if there are concerns about the adequacy of water purification procedures in dialysis facilities. Evidence of inadequate vitamin D nutrition, which is common among patients with CKD, should be sought by measuring serum 25-hydroxyvitamin D levels, and vitamin D nutrition should be restored by the administration of cholecalciferol or ergocalciferol if values are below 30 ng/mL. Long-term treatment with phenytoin and/or phenobarbital can lead to osteomalacia in nonuremic persons, and a higher prevalence of symptomatic bone disease has been reported in dialysis patients receiving these drugs. Persistent hypocalcemia and/or hypophosphatemia can lead to osteomalacia in some patients, but the disorder is seen much less frequently now that aluminum-containing medications are used sparingly and more attention has been given to maintaining adequate calcium and vitamin D nutrition among patients with CKD.

Mixed Lesion of Renal Osteodystrophy

Some patients with CKD have histologic features of both osteitis fibrosa and osteomalacia, a disorder known as the mixed lesion of renal osteodystrophy. There is biochemical evidence of secondary hyperparathyroidism, but other factors account for defects in skeletal mineralization. Persistent hypocalcemia and/or hypophosphatemia are found in some patients, and nutritional vitamin D deficiency is present in others. Mixed lesions of renal osteodystrophy can be seen in patients with osteitis fibrosa who are in the process of developing aluminum-related bone disease or in those with aluminum-related osteomalacia who respond favorably to treatment with deferoxamine (DFO) with increases in bone formation. Mixed renal osteodystrophy can thus represent a transitional state between the high-turnover lesions of secondary hyperparathyroidism and the low-turnover disorders of osteomalacia or adynamic bone.

The signs and symptoms of renal bone disease are rather nonspecific. Both the extent of various laboratory abnormalities and the severity of certain radiographic changes often fail to correspond to the clinical manifestations. Many patients report few symptoms despite striking disturbances in biochemical and x-ray parameters, but subtle complaints of musculoskeletal discomfort are common when sought by specific inquiry. Bone pain and muscle weakness are common. Skeletal deformities can develop in advanced cases, and extraskeletal calcifications are frequent.

Bone Pain

Bone pain is often present in patients with renal osteodystrophy. The onset is insidious with symptoms progressing gradually over many months or years. Pain is diffuse and nonspecific, and it is often aggravated by bearing weight and by changes in posture. When localized, the lower back, hips, and legs are affected most often. Pain in the heels or ankles may be a prominent complaint. Some patients experience an acute arthritis or periarthritis that is unrelieved by massage or the application of heat locally. Severe bone pain is more common in patients with aluminum related bone disease than in those with osteitis fibrosa, and it is a prominent clinical feature of bone aluminum toxicity. Nevertheless, some patients with advanced secondary hyperparathyroidism are incapacitated substantially. Physical examination is generally unremarkable unless skeletal fractures have occurred or unless bony deformities have developed.

Muscle Weakness

Proximal myopathy occurs in some patients with advanced renal failure. Symptoms appear slowly, and weakness and aching of the muscles are the most common manifestations. The physiologic basis of this disorder is not understood. Favorable clinical responses have been noted in some patients after treatment with calcitriol or 25-hydroxyvitamin D, following parathyroidectomy, after successful renal transplantation, or during treatment of aluminum-related bone disease with DFO. The role of abnormal vitamin D metabolism in the pathogenesis of uremic myopathy remains uncertain, but a careful evaluation must be done to exclude severe secondary hyperparathyroidism or bone aluminum toxicity. An empirical therapeutic trial of calcitriol or 25-hydroxyvitamin D is warranted in patients with persistent complaints of muscle pain and weakness.

Skeletal Deformities

In patients with aluminum-related bone disease, skeletal deformities are confined predominantly to the axial skeleton and include lumbar scoliosis, kyphosis, and distortion of the thoracic cage. Some persons with severe osteitis fibrosa develop rib deformities and pseudoclubbing.

Extraskeletal Manifestations

Several types of soft tissue calcification can be detected by radiographic examination. The most common are tumoral or periarticular calcifications. These are due mostly to amorphous deposits of calcium and phosphorus that sometimes are associated with acute periarticular inflammation and acute arthritis. Such calcifications commonly develop when serum phosphorus levels are markedly elevated or when the calcium–phosphorus ion product in serum is extremely high. They can resolve almost completely if serum phosphorus levels become better controlled. Although extraskeletal calcifications are more common with advancing age, they can occur at any age among those with CKD including children.

Visceral calcifications are rather infrequent, and their chemical composition may differ from those of other soft-tissue calcifications. The lungs, heart, kidneys, skeletal muscle, and stomach are involved most often. Pulmonary calcification can cause restrictive lung disease that may be progressive, and the disorder can persist even after successful kidney transplantation or parathyroidectomy.

Vascular calcification, specifically arterial calcification, is common among patients with CKD. The disorder is now recognized as an integral component of renal osteodystrophy, and it represents a risk factor for morbidity and mortality, predominantly from cardiovascular causes, among those undergoing dialysis.

Arterial calcifications among patients with CKD involve the medial layer of small- and medium-sized arteries predominantly, a lesion known as Monckerberg's sclerosis. Calcifications occur diffusely along the course of the vessel within the arterial wall, typically in associated with elastic collagen fibrils. Medial calcification is common in diabetic patients, and the radiographic appearance differs from the irregular, intermittent pattern that characterizes calcified intimal plaques due to atherosclerosis. It is best detected by lateral views of the ankle or anterior–posterior views of the hands or feet using magnification techniques with macroradioscopy. Imaging techniques such as electron beam computed tomography may be useful for detecting calcification in the coronary arteries or cardiac valves.

Medial wall calcification is usually asymptomatic, but the palpation of peripheral pulses and blood pressure measurements may be rendered difficult in affected limbs. Reductions in vascular compliance due to medial wall calcification adversely affect cardiovascular hemodynamics by raising systolic blood pressure, widening pulse pressure, and increasing pulse wave velocity. Such hemodynamic changes have been associated with worse cardiovascular outcomes.

It is now apparent that vascular calcification in patients with CKD is associated with serious adverse clinical outcomes including cardiovascular disease and high mortality rates from cardiovascular causes. In part, vascular calcification in such patients is related to disturbances in mineral metabolism such as phosphorus retention and hyperphosphatemia. Indeed, high serum phosphorus levels and elevated serum calcium concentrations have been identified as independent risk factors for death in adults undergoing regular hemodialysis. Episodes of hypercalcemia and calcium retention due to the use of large amounts of calcium as a phosphate-binding agent and from the administration of large doses of vitamin D sterols may also contribute.

Although soft-tissue and vascular calcification in end-stage renal disease (ESRD) has traditionally been thought to represent dystrophic calcification due predominantly to passive, physicochemical processes, there is now considerable evidence that vascular calcification is a regulated process that may be modulated by various genes and proteins normally involved in bone and mineral metabolism.

In some patients with extensive vascular calcification, ischemic necrosis of the skin, muscle, and/or subcutaneous tissues can develop. The condition is known variously as calciphylaxis or calcific uremic arteriolopathy (CUA). Its pathogenesis is not understood, but the disorder has been described in patients with CKD, in those receiving regular dialysis, and in renal transplant recipients. Most cases in early studies had advanced secondary hyperparathyroidism with markedly elevated PTH levels. Reports of clinical improvement after parathyroidectomy suggested that very high PTH levels played a pathogenic role. It is now evident, however, that CUA can occur in patients with adynamic renal osteodystrophy when plasma PTH levels are not substantially elevated.

Morbidity is severe and mortality rates are extremely high. Risk factors identified from various studies include female gender, increasing age, obesity, large doses of calcium-containing medications, and the use of the anticoagulant warfarin. It is quite possible that disturbances in the regulation of tissue-specific inhibitors of vascular calcification play a role in the pathogenesis of CUA.

Amyloidosis

Most patients who are treated with dialysis for more than 7–10 years develop deposits of a unique amyloid protein that is derived from β2M, a normal plasma constituent. Patients present with multiple bone cysts, pathologic fractures, carpal tunnel syndrome, scapulohumeral arthritis, and spondyloarthropathy. Involvement of the musculoskeletal system with bone pain and articular symptoms makes it difficult to separate dialysis-related amyloidosis from other forms of renal osteodystrophy.

The fibrils of β2M have a molecular weight of approximately 12,000 Da and are produced by many cells, particularly those of lymphoid tissue and other cells with high rates of turnover. The protein serves to stabilize the structure of the MHC class I antigen on cell surfaces, but it is released into the circulation when the complexes are shed from the cell membrane. Approximately 180–250 mg of β2M is generated normally each day. Nearly all β2M is filtered at the glomerulus and catabolized subsequently by renal tubular epithelial cells. It accumulates in plasma, however, in patients with advanced renal failure, and levels reach values 50 times greater than normal in dialysis patients with little or no residual renal function.

Histologically, β2M amyloid fibrils have an appearance that is similar to amyloid AA, but deposits of β2M occur predominantly in bones and joints, leading to musculoskeletal manifestations. Both the slow rate of appearance and the predilection for bone and articular structures suggest that elevated serum β2M levels do not fully account for the clinical syndrome observed in patients with chronic renal failure. Increases in age-related glycosylation products, certain specific proteases, and inhibitors of other proteases have each been suggested as factors that contribute to the deposition of β2M amyloid in bone and synovial tissues. Much less often, β2M amyloid deposits occur systemically, and these may be fatal.

The clinical features of amyloid deposition rarely appear before 5 years of dialysis therapy, and the disorder is more common among patients who start regular dialysis after the age of 50 years. Carpal tunnel syndrome is the most frequent clinical feature, but shoulder pain, other arthritic complaints, and cystic bone lesions are common. Deposits of β2M are found in periarticular structures, joints, bone, and tendon sheaths. Far less commonly, the liver, spleen, rectal mucosa, or blood vessels are involved.

Skeletal manifestations include generalized arthritis, erosive arthritis, and joint effusions. Scapulohumeral involvement with shoulder pain is a common clinical presentation. Generalized arthritis can lead to pain and stiffness, decreased joint mobility, joint effusions, and deformities. Pain is characteristically worse at night or when patients sit quietly for several hours during dialysis sessions. Motion of affected joints or activity provides temporary relief. Erosive arthritis can involve the metacarpophalangeal and interphalangeal joints, shoulders, wrists, and knees, sometimes with joint effusions. The cervical spine is the most common site of destructive spondyloarthropathy.

On skeletal radiographs, bone cysts are located most commonly at the ends of long bones, particularly in the femoral head and proximal humerus, but they may also occur in the metacarpal and carpal bones. Multiple cystic lesions are common, and sequential radiographs often demonstrate cyst enlargement over time. Cysts containing deposits of β2M may resemble the brown tumors of osteitis fibrosa, but their location and the presence of multiple rather than solitary cysts suggest that amyloid deposition is responsible. Cystic changes most commonly occur at sites of tendon insertions, and pathologically these may represent “amyloidomas” that have replaced trabecular bone. Fractures sometimes occur at these sites, and hip fractures in dialysis patients commonly arise at sites of β2M deposition. Examinations of the shoulder by ultrasound are a simple noninvasive method to assess progressive tendon involvement with β2M amyloid deposits.

The fraction of patients afflicted with amyloidosis increases progressively with the duration of dialysis therapy; thus, 70–80% of adult patients treated with hemodialysis for 10 or more years will have clinical features of β2M amyloidosis. The distinction between this disorder and either severe secondary hyperparathyroidism or aluminum-related bone disease can be difficult, and thorough clinical, biochemical, and radiographic evaluations are required. Amyloidosis due to β2M accumulation can coexist with either high-turnover or low-turnover skeletal lesions of renal osteodystrophy.

The clinical management of amyloidosis among patients undergoing dialysis has proven unsatisfactory. The carpal tunnel syndrome may respond to surgical correction, but it often reoccurs. The use of highly permeable dialysis membranes can moderately lower the serum levels of β2M, but there is no evidence that this intervention alters disease progression. The appearance of certain clinical features of dialysis amyloidosis may be delayed in patients treated from the onset of renal replacement therapy with dialysis membranes composed of polyacrylonitrile (PAN) membranes as compared to those treated with conventional cellulosic dialyzers. Successful renal transplantation is followed by symptomatic relief in most patients, but there is no evidence that β2M amyloid deposits in bone or other soft tissues actually regress after renal transplantation.

Biochemical Features

Serum calcium levels often are within the lower range of normal or modestly reduced in untreated patients with renal failure. After beginning treatment with dialysis, values usually rise and they may return to normal. The magnitude of the increase in serum calcium levels is in part related to the calcium concentration utilized in dialysis solutions. In patients treated with continuous ambulatory peritoneal dialysis (CAPD) who are not receiving vitamin D sterols, serum calcium levels are often within the normal range.

After calcium-containing, phosphate-binding agents were introduced as an alternative to aluminum-containing phosphate-binding medications, hypocalcemia became a less frequent problem in patients with CKD. Indeed, normal or high serum calcium levels are not uncommon among patients undergoing dialysis even in those who are not receiving vitamin D sterols. Such findings emphasize the importance of passive, vitamin D-independent intestinal calcium transport as a determinant of net intestinal calcium absorption when sufficiently large amounts of calcium are given orally to patients with renal failure.

The development of hypercalcemia in patients undergoing regular dialysis warrants prompt and thorough investigation. Common causes include marked hyperplasia of the parathyroid glands due to severe secondary hyperparathyroidism, adynamic renal osteodystrophy, treatment with calcitriol or other active vitamin D sterols, and the administration of large oral doses of calcium. Less frequent causes are aluminum-related bone disease, immobilization, malignancy, and granulomatous disorders such as sarcoidosis or tuberculosis where there is unregulated 1,25-dihydroxyvitamin D production by monocytes in granulomatous tissue. Basal serum calcium levels are generally higher and episodes of hypercalcemia occur more often in patients with adynamic bone than in persons with other skeletal lesions of renal osteodystrophy. Because skeletal calcium uptake is limited in the adynamic lesion, calcium entering the extracellular fluid from dialysate or following intestinal absorption cannot adequately be buffered in bone, and serum calcium levels rise. Lowering the doses of calcium-containing, phosphate-binding agents and decreasing temporarily the concentration of calcium in dialysate usually correct the hypercalcemia in such cases.

When the GFR falls below 15–20% of normal, hyperphosphatemia may develop. Phosphate-binding agents and dietary phosphorus restriction are usually required to avoid overt phosphate retention. Because the efficiency of phosphorus removal is limited during hemodialysis and peritoneal dialysis procedures, such measures are needed to adequately maintain serum phosphorus levels in most patients undergoing dialysis regularly without regard to the underlying type of renal bone disease.

In advanced renal failure, serum magnesium levels rise due to diminished renal magnesium excretion. Values are normal or slightly elevated when the concentration of magnesium in dialysate is kept between 0.5 and 0.8 mEq/L. The use of magnesium-containing laxatives or antacids can abruptly raise serum magnesium levels in patients with renal failure, and these medications should generally be avoided. It is prudent to monitor serum magnesium levels regularly if and when magnesium-containing medications are used.

Serum alkaline phosphatase values are fair markers of the severity of secondary hyperparathyroidism in patients with renal failure. Osteoblasts express large amounts of one isoenzyme of alkaline phosphatase, and serum levels are elevated when osteoblastic activity and bone formation are increased. High levels generally correspond to the extent of histologic change in patients with high-turnover lesions of renal osteodystrophy, and values frequently correlate with plasma PTH levels. Serum total alkaline phosphatase measurements may also be useful for monitoring the skeletal response to treatment with vitamin D sterols in patients with osteitis fibrosa. Values that decrease progressively over several months usually indicate histologic improvement.

Plasma aluminum levels are usually markedly elevated in patients with renal failure who have ongoing exposure to aluminum-containing medications or to inadequately purified dialysate. As such, plasma aluminum levels should be monitored regularly in patients undergoing maintenance dialysis, particularly in those who continue to use aluminum-containing, phosphate-binding medications. Plasma aluminum levels do not, however, serve as a reliable indicator of the extent of aluminum retention in tissues. Serum levels fall substantially within a few months after aluminum-containing medications are discontinued despite persistent aluminum retention in tissues. For these reasons, DFO infusions are a more reliable indicator of aluminum retention in tissues and provide useful information about the extent of tissue aluminum accumulation in patients undergoing dialysis.

Plasma PTH levels differ markedly according to type of renal bone disease, but double antibody immunometric assays generally provide reliable and reproducible results in patients with advanced renal failure. Indeed, plasma PTH measurements using first-generation immunometric assays are used widely for the initial diagnosis of renal osteodystrophy and to monitor therapy. The reference range of normal for these assays is generally in the range of 10–65 pg/mL, or 1–6 pM. Plasma PTH values are more useful than other serum biochemical markers for distinguishing between patients with secondary hyperparathyroidism and those with adynamic skeletal lesions. In untreated patients and in those receiving small daily oral doses of calcitriol, bone biopsy evidence of secondary hyperparathyroidism is found when plasma PTH levels exceed 250–300 pg/mL, or 25–30 pM. In contrast, values below 150 pg/mL, or 15 pM, and particularly levels below 100 pg/mL, or 10 pM, are typical for patients with adynamic renal osteodystrophy. Plasma PTH levels in the range of 150–300 pg/mL, or 2- to 4-fold higher than the upper limit of normal, generally correspond to normal rates of bone formation as documented by bone histomorphometry.

In contrast to the findings summarized previously for patients undergoing dialysis, plasma PTH levels that exceed the upper limit of normal are often associated with overt histologic evidence of secondary hyperparathyroidism in patients with earlier stages of CKD. Guidelines different from those that apply to patients treated with dialysis are thus required for patients with less advanced renal failure.

Until recently, the first-generation immunometric PTH assays that have been used widely in clinical chemistry for the past 15–20 years were thought to detect either predominantly or exclusively full-length PTH(1–84). It is now apparent, however, that these assays cross-react with other large amino-terminally truncated PTH fragments. In contrast, recently introduced second-generation immunometric PTH assays detect PTH(1–84) exclusively. When measured by second-generation assays, plasma PTH concentrations are on average 40–45% lower than values obtained using first-generation assays both in subjects with normal renal function and in those with ESRD. Several studies indicate, however, that values obtained with each assay are highly correlated.

The proper interpretation of PTH measurements in patients with renal failure depends largely on the extent to which values reflect bone histology as documented by bone biopsy. These relationships have been established for first-generation immunometric PTH assays, but only limited information is available using second-generation assays. It remains to be determined whether second-generation immunometric PTH will serve as better predictors of bone histology in patients with CKD.

The management of renal bone disease requires specific interventions that address selected pathogenic factors while limiting recognized risks. Key aspects of treatment include efforts to maintain serum calcium and phosphorus levels within the normal range and the judicious use of vitamin D sterols, calcimimetic agents, and phosphate-binding compounds. Additional considerations include the prevention of extraskeletal calcification, the avoidance of exposures to toxic agents such as aluminum and iron, and the selective use of chelating agents such as DFO to manage aluminum toxicity.

Diet

Adequate control of serum phosphorus levels is important for preventing soft-tissue calcification and for effectively managing secondary hyperparathyroidism in patients with advanced renal failure. The dietary intake of phosphorus ranges normally from 1.0 g/day to 1.3 g/day in healthy adults, but it must be reduced to 400–800 mg/day to prevent hyperphosphatemia in patients undergoing dialysis. Such diets are generally unpalatable, and long-term compliance is difficult to achieve. Consequently, phosphate-binding agents are usually employed together with dietary phosphorus restriction to control serum phosphorus levels when GFRs decrease to 15–20% of normal.

To diminish dietary phosphorus content effectively, the intake of dairy products must be curtailed. Phosphorus-restricted diets thus contain limited amounts of elemental calcium, often only 500–600 mg. As a result, many patients with CKD who abide strictly with current dietary recommendations ingest amounts of calcium that are insufficient to satisfy daily nutritional requirements. Modest dietary calcium supplementation is needed to achieve daily calcium intakes that approach 1200 mg as recommended by the World Health Organization. Concurrent therapy with calcium-containing or calcium-free phosphate-binding agents must be considered, however, when assessing overall calcium intake and the adequacy of calcium nutrition among patients with CKD.

Phosphate-Binding Agents

Phosphate-binding agents diminish intestinal phosphate absorption by forming insoluble complexes with phosphorus in the intestinal lumen. In the past, aluminum-containing medications were used widely, but these should now be employed sparingly, if at all, to avoid aluminum loading and aluminum toxicity. If they are used, the duration of treatment should be limited to a few months, and doses should be kept as low as possible. The concurrent administration of citrate-containing compounds must be avoided, and plasma aluminum levels should be monitored regularly.

Calcium carbonate and calcium acetate are the two most widely utilized phosphate-binding medications. They have similar efficacy. Calcium citrate can also be used as a phosphate-binding agent, but citrate enhances intestinal aluminum absorption in patients receiving aluminum-containing medications and should thus be used with caution. Calcium-containing agents, like all phosphate-binding compounds, are most effective when ingested with meals to maximize binding with phosphorus within the intestinal lumen. Such a dosing strategy also reduces the amount of unbound calcium that remains available for transport across the intestinal epithelium. Although reasonably effective for controlling serum phosphorus levels, very large amounts of elemental calcium are required to control hyperphosphatemia in patients undergoing dialysis regularly. The total daily intake of elemental calcium usually exceeds 1500–2000 mg among patients who use calcium-containing phosphate-binding medications exclusively, and it may reach 4–6 g or more. Episodes of hypercalcemia thus represent a major treatment-related side effect.

The use of very large does of calcium as a phosphate-binding agent has been associated with evidence of softtissue and vascular calcification among patients undergoing dialysis regularly. As a result, alternative phosphate-binding strategies that limit cumulative calcium intake to 1500–2000 mg/day from both dietary and medicinal sources have been recommended. Because of the limited efficacy of calcium salts as phosphate-binding agents, the feasibility of such strategies is dependent largely on the availability of calcium-free, phosphate-binding agents. Several are available currently including sevelamer and lanthanum carbonate.

Sevelamer hydrochloride, or hydrogel of cross-linked polyallylamine hydrochloride (RenaGel), is an ion-exchange polymer that was designed specifically as a phosphate-binding agent. It does not contain calcium or aluminum. In short-term clinical trials, sevelamer has been shown to be as effective as calcium acetate for controlling serum phosphorus levels with a substantially lower incidence of episodes of hypercalcemia. In studies of longer duration, total daily doses averaging 5–6 g were sufficient to maintain serum phosphorus levels at approximately 5.8–6.0 mg/dL, or 1.8–2.0 mM, among patients undergoing hemodialysis. Interestingly, the serum levels of total cholesterol and low-density lipoprotein (LDL) cholesterol decreased by 20–30% during treatment, whereas high-density lipoprotein (HDL) cholesterol levels rose. In patients with chronic renal failure who do not require dialysis, modest reductions in serum carbon dioxide levels, which reflect decreases in plasma bicarbonate concentrations, may occur during treatment with sevelamer. The change is probably due to the release of protons from the resin during phosphate binding.

Lanthanum carbonate is another calcium-free, phosphate-binding agent that is now available for use clinically. Its capacity to bind phosphorus in vitro is equivalent to that of aluminum hydroxide and exceeds that of both calcium carbonate and calcium acetate. Moreover, variations in pH have much less effect on the phosphate-binding capacity of lanthanum carbonate in vitro than on calcium-containing compounds. In large clinical trials, lanthanum carbonate has been shown to be an effective phosphate-binding agent among patients undergoing long-term dialysis.

Although lanthanum absorption from the gastrointestinal tract was thought originally not to occur, a small percentage of ingested lanthanum is absorbed. As compared to aluminum, the fractional absorption of lanthanum is several orders of magnitude lower. Nevertheless, lanthanum is detectable in plasma and low levels of the metal are found in bone among patients treated for as long as 2 years. Serial assessments of bone biopsies from such patients have thus far revealed no untoward effects on bone histology, skeletal mineralization, or bone cell activity.

Magnesium carbonate has been reported to be an effective phosphate binder when used together with magnesium-free dialysate in patients undergoing regular hemodialysis. Unfortunately, gastrointestinal side effects, particularly diarrhea, occur often when magnesium-containing compounds are used regularly as phosphate-binding agents.

Vitamin D Sterols

Despite efforts to control phosphorus retention and hyperphosphatemia and to optimize calcium nutrition, many patients who require ongoing treatment with dialysis develop secondary hyperparathyroidism. Until the introduction of calcimimetic agents, vitamin D sterols represented the only definitive pharmacologic intervention to treat the disorder. Although calcifediol, or 25-hydroxyvitamin D3 , 1α-hydroxyvitamin D3, and dihydrotachysterol have all been shown to be effective therapeutically, calcitriol and other recently introduced vitamin D sterols such as paricalcitol and doxercalciferol are used much more widely for treating secondary hyperparathyroidism among patients undergoing dialysis regularly.

Daily oral doses of calcitriol are effective in many patients with symptomatic renal bone disease due to secondary hyperparathyroidism. Treatment is started using a dose of 0.25 μg/day and daily doses are adjusted upward periodically if serum calcium and phosphorus levels remain within acceptable limits. Bone pain diminishes, muscle strength and gait-posture improve, and osteitis fibrosa frequently resolves either partially or completely. When measured using reliable assays, PTH levels decrease in those who respond favorably to treatment. Similar findings have been reported in patients given daily oral doses of 1α-hydroxyvitamin D3 , or alfacalcidol, which undergoes 25-hydroxylation in the liver to form calcitriol.

Doses of oral calcitriol in most clinical trials have ranged between 0.25 and 1.5 μg/day. Hypercalcemia is the most common side effect of treatment, but most adult patients tolerate daily doses of 0.25–0.50 μg without marked increases in serum calcium levels. Pediatric patients may require somewhat larger daily doses per unit of body weight. Growth velocity has been reported to increase during calcitriol therapy in children with severe renal bone disease.

Oral calcitriol therapy is now used relatively infrequently in patients treated with regular hemodialysis because vitamin D sterols can be given conveniently by the intravenous route during three times a week dialysis procedures. Parenteral dosing strategies ensure patient compliance, and they produce very high plasma sterol levels shortly after intravenous doses, which have been suggested to enhance the suppressive actions of vitamin D on PTH synthesis. Evidence from clinical studies to support this contention is limited. Intermittent as opposed to daily vitamin D administration may, however, decrease the effect of vitamin D to promote intestinal calcium transport. Calcitriol, paricalcitol, and doxercalciferol are all available as preparations that can be given intravenously.

Large intermittent oral doses of calcitriol have been used to treat secondary hyperparathyroidism in patients undergoing peritoneal dialysis where repeated parenteral dosing is impractical. When given two or three times per week, the cumulative weekly dose of calcitriol that can be achieved is somewhat greater than with daily therapy. Dosage regimens have ranged from 0.5–1.0 μg to 3.5–4.0 μg three times a week or from 2.0 to 5.0 μg twice weekly. Small doses should be used initially for reasons of safety, but upward adjustments to the dose can be made subsequently if serum calcium and phosphorus levels remain controlled adequately. It is not yet known whether intermittent calcitriol therapy is more effective than treatment with daily oral doses of calcitriol for managing secondary hyperparathyroidism among patients undergoing peritoneal dialysis.

The development of hypercalcemia during calcitriol therapy may be helpful in judging the status of bone remodeling among patients with renal osteodystrophy. When hypercalcemia occurs after several months of treatment and when previously elevated serum PTH and alkaline phosphatase levels have returned toward normal, it is likely that osteitis fibrosa has improved and that bone remodeling has diminished substantially. In contrast, episodes of hypercalcemia occurring during the first few weeks of treatment with calcitriol suggest either preexisting low-turnover bone disease, which in some cases is due to bone aluminum deposition, or severe secondary hyperparathyroidism. Bone biopsy and measurements of bone aluminum content may be needed to exclude aluminum-related bone disease. If there is biochemical evidence of progressive or advanced secondary hyperparathyroidism, parathyroidectomy is required.

In adult hemodialysis patients, the intravenous administration of calcitriol three times a week effectively lowers serum PTH levels in those with mild to moderate secondary hyperparathyroidism. As mentioned previously, somewhat larger cumulative weekly doses of calcitriol are achievable using intermittent parenteral dosage regimens as compared to daily oral dosing.

Increases in serum calcium and phosphorus levels often limit the doses of calcitriol that can be given safely to patients undergoing dialysis, particularly in those who are also ingesting large oral doses of calcium as a phosphate-binding agent. Because of ongoing concerns about the possibility of aggravating soft-tissue and vascular calcification during the medical management of secondary hyperparathyroidism with vitamin D sterols, the use of intravenous calcitriol has been superceded largely by treatment with new analogs of vitamin D such as paricalcitol and doxercalciferol. Both are vitamin D2 derivatives. Each has been shown to effectively lower plasma PTH levels by 50–60% over 12–16 weeks of treatment in hemodialysis patients with secondary hyperparathyroidism, whereas serum calcium and phosphorus concentrations increased only modestly. It is possible therefore that paricalcitol and doxercalciferol provide a wider margin of safety in managing calcium and phosphorus metabolism during the treatment of secondary hyperparathyroidism among patients with CKD. Indeed, results from one comparative study of 12 months duration indicate that the frequency of persistent episodes of hypercalcemia and hyperphosphatemia was modestly lower among patients receiving paricalcitol compared to those treated with calcitriol.

Reductions in plasma PTH levels are used most often to assess the therapeutic efficacy of vitamin D sterols in patients with secondary hyperparathyroidism. Although serum PTH levels generally reflect the severity of bone disease in untreated patients and in those receiving small daily oral doses of calcitriol, similar relationships may not apply during the treatment of secondary hyperparathyroidism with large intermittent doses of vitamin D sterols given twice or three a week. Bone formation and turnover have been shown to fall strikingly during intermittent calcitriol therapy, and a substantial proportion of patients develops adynamic renal osteodystrophy. In some, adynamic lesions occur after plasma PTH levels fall substantially. In others, however, decreases in bone formation can occur as documented by bone histomorphometry despite persistent elevations in plasma PTH levels. Such findings suggest that large intermittent doses of calcitriol diminish osteoblastic activity and lower bone formation rates directly by PTH-independent mechanisms. Accordingly, plasma PTH levels should be monitored regularly during intermittent calcitriol therapy, and the dose of calcitriol should be reduced when serum PTH levels fall to values four or five times the upper limit of normal to diminish the risk of suppressing PTH values excessively and inducing adynamic bone. It is not known whether new vitamin D analogs affect osteoblastic activity and lower bone formation in a manner similar to that described during intermittent calcitriol therapy. Interval changes in bone histology after treatment with paricalcitol and doxercalciferol have yet to be reported.

Calcimimetic Agents

Calcimimetic agents are small organic molecules that function as allosteric activators of the CaSR. In parathyroid cells, they lower the threshold for receptor activation by extracellular calcium ions and diminish PTH secretion. When given orally to patients with secondary hyperparathyroidism, plasma PTH levels decline abruptly within 1–2 hours after drug administration. Calcimimetic compounds thus represent a novel way of altering parathyroid gland function. They represent a new class of therapeutic agents for secondary hyperparathyroidism with a mechanism of action that differs fundamentally from that of the vitamin D sterols, and they provide a second, previously unavailable, pharmacologic intervention for managing the disorder among patients with CKD.

Clinical trials have demonstrated that the calcimimetic agent cinacalcet hydrochloride effectively lowers plasma PTH levels without increasing serum calcium or phosphorus concentrations in patients with secondary hyperparathyroidism who are managed with either hemodialysis or peritoneal dialysis. Indeed, serum calcium and phosphorus concentrations and values for the calcium–phosphorus ion product in serum often decrease as plasma PTH levels decline during treatment. The ability of cinacalcet to lower plasma PTH levels without increasing serum calcium and phosphorus levels is noteworthy for several reasons.

First, considerable evidence has accumulated to suggest that persistent elevations in serum calcium and phosphorus levels are associated with adverse clinical outcomes in general and with cardiovascular events in particular among patients undergoing long-term dialysis. Second, recent guidelines for managing bone disease and mineral metabolism among patient with CKD set more stringent limits, which differ substantially from previous recommendations, with respect to the upper limits for serum calcium and phosphorus levels that are considered to be acceptable among patients who require renal replacement therapy. Such recommendations are based largely upon concerns about the long-term safety of various therapeutic interventions for secondary hyperparathyroidism, which include the use of large intravenous doses of vitamin D sterols and large oral doses of calcium as a phosphate-binding agent. Within this context, the use of vitamin D sterols becomes quite challenging, and many patients with secondary hyperparathyroidism are precluded from treatment because calcium and phosphorus metabolism cannot be controlled adequately to permit their safe therapeutic use.

Parathyroidectomy

Parathyroid surgery may be required to control secondary hyperparathyroidism in many patients undergoing long-term dialysis. The likelihood of parathyroidectomy increases progressively as a function of the number of years of treatment with dialysis, and annual parathyroidectomy rates among those undergoing dialysis regularly have not changed appreciably over the past 10–15 years. Severe secondary hyperparathyroidism should be documented thoroughly by biochemical, radiographic, and bone histologic criteria, if necessary, before surgery is undertaken. The diagnosis of aluminum-related bone disease must be considered and excluded before proceeding with parathyroidectomy because the disorder may worsen after surgery.

Specific indications for parathyroidectomy include persistent hypercalcemia together with persistently elevated plasma PTH levels, intractable pruritus that does not respond to intensive dialysis or to other medical interventions, worsening extraskeletal calcifications and/or persistent hyperphosphatemia despite the continued use of dietary phosphorus restriction and phosphate-binding agents, severe bone pain or fractures, and the development of calciphylaxis with biochemical evidence of ongoing excess PTH secretion. Other causes of hypercalcemia such as sarcoidosis, malignancy, or the intake of excessive amounts of calcium or vitamin D must be considered and excluded.

Uncertainties persist about the use of subtotal versus total parathyroidectomy among patients with secondary hyperparathyroidism due to CKD. The disorder reoccurs in 15–30% of those who undergo subtotal parathyroidectomy, which is likely due to ongoing hyperplasia in remnant parathyroid tissue. This observation together with the ability to effectively manage postoperative hypocalcemia with calcitriol and other vitamin D sterols renders total parathyroidectomy a viable approach to long-term management. For patients who may subsequently undergo renal transplantation, however, the better preservation of calcium metabolism in general and the lower risk of persistent hypocalcemia after renal function is restored favor subtotal rather than total parathyroidectomy.

It is generally not advisable to implant remnant parathyroid tissue into subcutaneous tissue in the forearm or other sites in an effort to preserve parathyroid gland function after surgery. Such grafts may exhibit autonomous secretory behavior, and they occasionally spread locally into surrounding tissues and cause recurrent hyperparathyroidism. Adequate surgical resection can be difficult.

Management of Aluminum Intoxication

The clinical manifestations and histologic features of aluminum-related bone disease improve during treatment with DFO in patients undergoing regular dialysis. Aluminum removal during hemodialysis and peritoneal dialysis increases substantially after DFO is given either intravenously or subcutaneously before dialysis procedures. Clinical benefit has been reported in a large proportion of patients with severe bone disease after 4–10 months of treatment.

Biochemical changes during DFO treatment include reductions in serum calcium levels and increases in serum alkaline phosphatase values, findings consistent with improvements in skeletal mineralization and osteoblastic activity. Plasma PTH levels rise modestly in many patients, but it is not known whether this change is due to aluminum removal from the parathyroid glands or to a fall in serum calcium concentrations. Sequential bone biopsies generally show increases in bone formation and improvements in mineralization. The amount of surface stainable aluminum in bone decreases in most patients who improve with treatment, but patients who have undergone previous parathyroidectomy respond less well or not at all.

Serious, often lethal, infections with Rhizipus and Yersinia spp. can develop in dialysis patients given DFO. The chelation of iron by DFO enhances iron delivery to certain organisms, increasing their pathogenic potential. As such, DFO should be used cautiously and judiciously in the treatment of aluminum intoxication among patients undergoing dialysis.

DFO should be given only to patients with symptomatic aluminum intoxication, and evidence of tissue toxicity should be documented fully before treatment is begun. Doses of DFO should not exceed 0.5–1.0 g/week, and plasma aluminum levels should be monitored regularly. Subcutaneous administration avoids the high serum levels of ferrioxamine that can occur after intravenous doses, and this therapeutic approach may limit the risk of developing opportunistic infections. In asymptomatic patients who have evidence of bone aluminum deposition, bone histology and bone formation often improve solely by withdrawing aluminum-containing medications and using calcium-containing compounds to manage phosphorus retention.

This work was supported in part by USPHS Grant DK-60107.