Calciotropic hormones and the skeleton in uraemia

Lewin, Ewa; Ølgaard, Klaus

doi:10.1046/j.1365-2362.1999.00500.x

Cited by 3 publications

(4 citation statements)

References 14 publications

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“…Secondary hyperparathyroidism develops early in renal insufficiency and may affect the function of several organs besides the skeleton (17)(18)(19). The stimuli for the development of secondary hyperparathyroidism that are relevant to renal failure are hypocalcemia, hyperphosphatemia, and low levels of 1,25(OH) 2 D (calcitriol) (20)(21)(22)(23)(24).…”

Section: Enhanced Pth Biosynthesis and Secretion In Uremiamentioning

confidence: 99%

Basic Science and Dialysis: Parathyroid Growth and Suppression in Renal Failure

Lewin

Huan

Ølgaard

2006

Seminars in Dialysis

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In advanced uremia, parathyroid hormone (PTH) levels should be controlled at a moderately elevated level in order to promote normal bone turnover. As such, a certain degree of parathyroid hyperplasia has to be accepted. Uremia is associated with parathyroid growth. In experimental studies, proliferation of the parathyroid cells is induced by uremia and further promoted by hypocalcemia, phosphorus retention, and vitamin D deficiency. On the other hand, parathyroid cell proliferation might be arrested by treatment with a low-phosphate diet, vitamin D analogs, or calcimimetics. When established, parathyroid hyperplasia is poorly reversible. There exists no convincing evidence of programmed parathyroid cell death or apoptosis in hyperplastic parathyroid tissue or of involution of parathyroid hyperplasia. However, even considerable parathyroid hyperplasia can be controlled when the functional demand for increased PTH levels is removed by normalization of kidney function. Today, secondary hyperparathyroidism can be controlled in patients with long-term uremia in whom considerable parathyroid hyperplasia is to be expected. PTH levels can be suppressed in most uremic patients and this suppression can be maintained by continuous treatment with phosphate binders, vitamin D analogs, or calcimimetics. Thus modern therapy permits controlled development of parathyroid growth. When nonsuppressible secondary hyperparathyroidism is present, nodular hyperplasia with suppressed expression of the calcium-sensing receptor (CaR) and vitamin D receptor (VDR) has been found in most cases. An altered expression of some autocrine/paracrine factors has been demonstrated in the nodules. The altered quality of the parathyroid mass, and not only the increased parathyroid mass per se, might be responsible for uncontrollable hyperparathyroidism in uremia and after kidney transplantation.

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Section: Enhanced Pth Biosynthesis and Secretion In Uremiamentioning

confidence: 99%

Basic Science and Dialysis: Parathyroid Growth and Suppression in Renal Failure

Lewin

Huan

Ølgaard

2006

Seminars in Dialysis

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“…ABD therefore leaves patients with an inability to respond appropriately to episodes of hypercalcemia. The occurrence of skeletal resistance to the effects of PTH also likely reflects an alteration in the level of inhibitors or activators of bone formation including, vitamin D, phosphorus, growth factors, cytokines, and various transcription factors (5,(7)(8)(9)(10)(11).…”

Section: Spectrum Of Renal Osteodystrophymentioning

confidence: 99%

“…The secretion of PTH is generally increased in response to renal failure, an increase that is thought to compensate for alterations in mineral metabolism caused by the loss of renal mass and function. The loss of kidney function results in an accumulation of metabolic fragments of PTH and PTHrP, some of which may adversely affect bone metabolism (10, 13).…”

Section: Parathyroid Hormonementioning

confidence: 99%

Regulation of Bone Remodeling: Impact of Novel Therapies

Hercz

2001

Seminars in Dialysis

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The kidneys serve as both an endocrine organ and as a target of endocrine action, with the aim of controlling mineral and water balance. Hormones and other key metabolites regulate mineral homeostasis by altering gene function directly or by initiating a sequence of events, leading ultimately to a change in enzyme function. Two of these hormones, parathyroid hormone (PTH) and calcitriol (the active form of vitamin D), interact in multiple tissues in the body to regulate the flux of calcium and phosphorus between extra- and intracellular compartments. Changes in the concentration of PTH and vitamin D, or the interaction of these with other factors, lead to the aberrant regulation of calcium and phosphorus. Among other effects, this aberrant regulation leads to pathologic changes in bone metabolism. The pathology of renal bone disease varies along a spectrum from disorders of low turnover to those of high turnover. This spectrum reflects the results of therapeutic intervention, hormone balances, and other causes. Effective management of renal bone disease therefore requires thorough evaluation of relevant risk factors, measurement of biochemical markers of bone remodeling, and determination of the physical status of bone tissue either by bone mineral density or bone biopsy. Subsequent therapeutic intervention with newer vitamin D compounds, novel phosphate binders, calcimimetics, and the use of alternative dialysis modalities offer hope in normalizing bone remodeling and mineral balance. The human skeleton functions in two capacities: the storage of minerals and structural support of the body. It is the only tissue that behaves as both a major source and a sink of calcium (Ca) and phosphorus (P). Healthy bone is a composite of a collagenous matrix embedded with crystals of hydroxyapatite. On the surface of bone and within the calcified matrix are specialized cells that build and maintain the tissue, and facilitate the movement of Ca and P into and out of serum. Bone undergoes remodeling in response to either damage from mechanical strain or as part of the normal cycle of bone renewal. The process involves distinct steps of cellular activation, bone resorption, and subsequent bone formation. It is a relatively slow process that takes several months, and at any one time occurs at many different sites along the bone surface. Systemic factors, such as PTH and vitamin D, regulate the resorption and formation of bone, and thus the systemic movement of Ca and P. However, during conditions of stress and disease, other factors may also play a role. In patients with chronic renal disease, the balance of Ca and P is profoundly disturbed. This disruption and the compensatory changes that occur in response alter the normal processes of bone metabolism.

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“…The second component is the effector system of calcium-translocating cells in the kidneys, bones, and intestine, which respond to these calciotropic hormones. The relationship between Ca 2+ and the calciotropic hormones is still debated (3,5,(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Prevention of Uremic Bone Disease Using Calcimimetic Compounds

Ølgaard

Lewin²

2001

Annu. Rev. Med.

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The discovery, characterization, and cloning of the calcium-sensing receptor (CaR) in 1993 was soon followed by the creation of a new type of drug, the calcimimetics-NPS R-568 and NPS R-467-which are small phenylalkylamine derivative compounds that act as CaR agonists and increase the sensitivity of the CaR to activation by extracellular calcium (Ca2+). As expected, these compounds turned out to have a significant effect on the Ca2+/parathyroid hormone (PTH) relationship, resulting in a dramatically greater suppression of the PTH level than would otherwise occur at the actual extracellular Ca2+ levels. Renal osteodystrophy (RO) due to secondary hyperparathyroidism (HPT) in chronic renal failure was an obvious target for studying the effects of NPS R-568. In a study on experimental animals, the results clearly showed that this first generation of calcimimetics, NPS R-568, had an acute dose-dependent and short-lived suppressive effect on PTH secretion from the parathyroid glands. A similar effect was found in patients with chronic renal failure and secondary HPT. At the same time, the calcimimetics induced a slight degree of hypocalcemia. Such a significant suppressive effect on PTH secretion would be expected to result in therapeutic potential for a preventive or therapeutic effect on the RO accompanying chronic uremia. Administration would probably be in close concert with present strategies, phosphate binders and vitamin D analogs. A wide distribution of CaRs have now been demonstrated in the body, and an important question is how calcimimetics will affect the function of different tissues and organs when used for long-term treatment or prevention of secondary HPT and RO. Although relatively few experimental and clinical investigations have been completed, they clearly confirm the suppressive effect of calcimimetics on PTH secretion. In rats with experimental chronic renal failure, a significant and beneficial effect on the prevention of RO has been demonstrated. The effect of calcimimetic compounds is presently being evaluated in humans. Besides induction of hypocalcemia, the adverse effects in these mainly short-term studies have been few. Future studies with calcimimetics will further define the physiology and pathophysiology of the CaR and the long-term benefit of calcimimetic compounds in patients with chronic renal failure.

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Calciotropic hormones and the skeleton in uraemia

Cited by 3 publications

References 14 publications

Basic Science and Dialysis: Parathyroid Growth and Suppression in Renal Failure

Basic Science and Dialysis: Parathyroid Growth and Suppression in Renal Failure

Regulation of Bone Remodeling: Impact of Novel Therapies

Prevention of Uremic Bone Disease Using Calcimimetic Compounds

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