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Metabolic Bone Disease in Chronic Kidney Disease -
Kidney-Bone-Cardio Connection
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Download the PDF here
Kevin J. Martin and Esther A. González
JASN March 2007
"in human CKD, many patients have significant proteinuria, which will lead to the loss of vitamin D–binding protein with its bound ligand in the urine and contribute to the high incidence of vitamin D deficiency, manifested by low levels of 25-hydroxyvitamin D, in this clinical setting (37). Substrate limitation could impair the ability of the diseased kidney to increase calcitriol production.......As kidney disease advances, there are other factors that can limit the actions of calcitriol......Decreased levels of calcitriol also may contribute to parathyroid abnormalities.
Metabolic bone disease in patients with kidney disease often is asymptomatic, and symptoms appear only late in its course. Many of the symptoms are nonspecific and include pain and stiffness in joints, spontaneous tendon rupture, predisposition to fracture, and proximal muscle weakness. A similar set of symptoms may be seen in both the low- and high-turnover type of skeletal abnormality. It is important to emphasize that the absence of clinical signs and symptoms of metabolic bone disease do not underscore the importance of these abnormalities, because many of the processes that contribute to the underlying metabolic bone disease also have consequences at extraskeletal sites, and the control of these processes is important to decrease morbidity and mortality.
Extraskeletal calcifications, particularly involving the vasculature, and calcification of the skin and calciphylaxis also may be seen. Cardiovascular calcification is extremely common and important in patients with kidney disease, in whom it develops and progresses rapidly and predicts a variety of adverse outcomes. The various types of metabolic bone disease and associated mineral disorders may contribute to this."
excerpts
Abstract
Metabolic bone disease is a common complication of chronic kidney disease (CKD) and is part of a broad spectrum of disorders of mineral metabolism that occur in this clinical setting and result in both skeletal and extraskeletal consequences. Detailed research in that past 4 decades has uncovered many of the mechanisms that are involved in the initiation and maintenance of the disturbances of bone and mineral metabolism and has been translated successfully from "bench to bedside" so that efficient therapeutic strategies now are available to control the complications of disturbed mineral metabolism. Recent emphasis is on the need to begin therapy early in the course of CKD. Central to the assessment of disturbances in bone and mineral metabolism is the ability to make an accurate assessment of the bone disease by noninvasive means. This remains somewhat problematic, and although measurements of parathyroid hormone are essential, recently recognized difficulties with these assays make it difficult to provide precise clinical practice guidelines for the various stages of CKD at the present time. Further research and progress in this area continue to evaluate the appropriate interventions to integrate therapies for both the skeletal and extraskeletal consequences with a view toward improving patient outcomes.
Metabolic bone disease is a common complication of chronic kidney disease (CKD) and is part of a broad spectrum of disorders of mineral metabolism that occur in this clinical setting. Alterations in the control mechanisms for calcium and phosphorus homeostasis occur early in the course of CKD and progress as kidney function decreases; if left untreated, then alterations can result in significant consequences. The disorders of bone have to be considered not only with regard to the bone itself but also with regard to the consequences of disturbed mineral metabolism at extraskeletal sites, including the vasculature. In recognition of the broad spectrum of disorders of mineral metabolism in this clinical setting, it has been recommended that terms such as "renal osteodystrophy" and "renal bone disease" give way to the term "CKD-mineral and bone disorder" to describe this broad clinical syndrome that develops as a systemic disorder of mineral and bone metabolism as a result of CKD that can be manifested by any one or a combination of the following: (1) Abnormalities of calcium, phosphorus, parathyroid hormone (PTH), and vitamin D metabolism; (2) abnormalities of bone turnover, mineralization, volume, linear growth, and strength; and (3) vascular or soft tissue calcification (1).
The abnormalities in bone in the setting of CKD include the effects of high levels of PTH on bone, which results in the high-turnover bone disease osteitis fibrosa. In addition, in the setting of CKD, a different skeletal abnormality known as adynamic bone, which is characterized by an extremely low bone turnover, may occur. Some cases may demonstrate mineralization defects and show frank osteomalacia. This wide spectrum of skeletal abnormality can give rise to a variety of mixed patterns, with elements of the effects of hyperparathyroidism on bone together with mineralization defects, and is known as mixed renal osteodystrophy. In addition, other systemic processes that may affect the skeleton, such as the accumulation of β-2 microglobulin or the systemic effects of postmenopausal osteoporosis or steroid-induced osteoporosis, may complicate the picture. A wide variety of disturbances of bone metabolism may occur in the setting of CKD. An understanding of the pathogenesis of these abnormalities then becomes essential to design a rational approach to their treatment and to the prevention of complications.
Clinical Signs and Symptoms of Metabolic Bone Disease in CKD
Metabolic bone disease in patients with kidney disease often is asymptomatic, and symptoms appear only late in its course. Many of the symptoms are nonspecific and include pain and stiffness in joints, spontaneous tendon rupture, predisposition to fracture, and proximal muscle weakness. A similar set of symptoms may be seen in both the low- and high-turnover type of skeletal abnormality. It is important to emphasize that the absence of clinical signs and symptoms of metabolic bone disease do not underscore the importance of these abnormalities, because many of the processes that contribute to the underlying metabolic bone disease also have consequences at extraskeletal sites, and the control of these processes is important to decrease morbidity and mortality.
Extraskeletal calcifications, particularly involving the vasculature, and calcification of the skin and calciphylaxis also may be seen. Cardiovascular calcification is extremely common and important in patients with kidney disease, in whom it develops and progresses rapidly and predicts a variety of adverse outcomes. The various types of metabolic bone disease and associated mineral disorders may contribute to this. The processes that are responsible for vascular calcification are the focus of recent research (76,77). The evidence now suggests that vascular calcification is an active, regulated process that has many similarities to the process of skeletal mineralization. Studies suggest that the normal vessel wall expresses proteins that inhibit calcification such as matrix Gla protein. In addition, circulating proteins such as fetuin-A are produced at remote sites and act to inhibit soft tissue calcification systemically. However, alterations of these proteins may lead to a seeming transformation of vascular smooth muscle cells into osteo/chondrocytic-like cells that then facilitate calcification. Both clinical and basic research findings indicate an inverse relationship between bone mineralization and vascular calcification. The mechanisms that link these two processes are a topic of active investigation. A detailed discussion of extraskeletal calcification is beyond the scope of this review.
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