Renal osteodystrophy for nonnephrologists.
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Bone Diseases↗
Biomedical subjects
William G Goodman
Publications and source records attributed to William G Goodman.
PTH(1-84)/PTH(7-84): a balance of power.
This review considers many new basic and clinical aspects of parathyroid hormone (PTH). We focus especially on the identification of PTH fragments and how they may relate to renal failure, diagnosis, and treatment of secondary hyperparathyroidism and renal osteodystrophy. The biosynthesis and metabolism of PTH, measurement of circulating forms of PTH, the effects of PTH on receptor activation and turnover, the relationship between PTH levels and bone turnover in renal failure in humans, and the involvement of PTH in experimental models of renal failure are discussed. Despite these developments in understanding the etiology of renal failure and the availability of new assays for bioactive PTH, no adequate surrogate for bone biopsy and quantitative bone histomorphometry has been developed.
Amino Acid Sequence↗
Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl.
BACKGROUND: Patients with secondary hyperparathyroidism often require therapy that provides long-term control of parathyroid hormone concentrations without increasing calcium and phosphorus concentrations. Cinacalcet modulates the calcium-sensing receptor on the parathyroid gland to reduce secretion of parathyroid hormone and lower serum calcium, phosphorus and calcium-phosphorus product in haemodialysis patients. METHODS: Dialysis patients with secondary hyperparathyroidism [parathyroid hormone (PTH) level > or =300 pg/ml] who were enrolled in one of four phase 2 placebo-controlled studies were eligible to enroll in an open-label extension study in which all patients received cinacalcet. For this extension study, cinacalcet was initiated at 30 mg in all patients and the dose was escalated to a maximum of 180 mg once daily if PTH concentrations were >250 pg/ml. Use of concomitant vitamin D sterols and phosphate binders was not restricted. RESULTS: The analysis of all patients (n = 59) completing 100 weeks of cinacalcet treatment showed long-term control of PTH and calcium-phosphorus product. Approximately 55% achieved a PTH concentration < or =300 pg/ml at the week-100 study visit, and approximately 60% had at least a 30% reduction in PTH from baseline. Serum calcium, phosphorus and the calcium-phosphorus product did not increase during the study. Concomitant vitamin D sterol and phosphate binder therapy remained stable. Cinacalcet was safe and generally well tolerated at doses up to 180 mg/day. CONCLUSIONS: In this long-term study, cinacalcet effectively sustained reductions in PTH for up to 3 years without increasing concentrations of serum calcium, phosphorus or calcium-phosphorus product.
Adult↗
Sevelamer controls parathyroid hormone-induced bone disease as efficiently as calcium carbonate without increasing serum calcium levels during therapy with active vitamin D sterols.
Little is known about the impact of various phosphate binders on the skeletal lesions of secondary hyperparathyroidism (2 degrees HPT). The effects of calcium carbonate (CaCO3) and sevelamer were compared in pediatric peritoneal dialysis patients with bone biopsy-proven 2 degrees HPT. Twenty-nine patients were randomly assigned to CaCO3 (n = 14) or sevelamer (n = 15), concomitant with either intermittent doses of oral calcitriol or doxercalciferol for 8 mo, when bone biopsies were repeated. Serum phosphorus, calcium, parathyroid hormone (PTH), and alkaline phosphatase were measured monthly. The skeletal lesions of 2 degrees HPT improved with both binders, and bone formation rates reached the normal range in approximately 75% of the patients. Overall, serum phosphorus levels were 5.5 +/- 0.1 and 5.6 +/- 0.3 mg/dl (NS) with CaCO3 and sevelamer, respectively. Serum calcium levels and the Ca x P ion product increased with CaCO3; in contrast, values remained unchanged with sevelamer (9.6 +/- 01 versus 8.9 +/- 0.2 mg/dl; P < 0.001, respectively). Hypercalcemic episodes (>10.2 mg/dl) occurred more frequently with CaCO3 (P < 0.01). Baseline PTH levels were 980 +/- 112 and 975 +/- 174 pg/ml (NS); these values decreased to 369 +/- 92 (P < 0.01) and 562 +/- 164 pg/ml (P < 0.01) in the CaCO3 and the sevelamer groups, respectively (NS between groups). Serum alkaline phosphatase levels also diminished in both groups (P < 0.01). Thus, treatment with either CaCO3 or sevelamer resulted in equivalent control of the biochemical and skeletal lesions of 2 degrees HPT. Sevelamer, however, maintained serum calcium concentrations closer to the lower end of the normal physiologic range, thereby increasing the safety of treatment with active vitamin D sterols.
Adolescent↗
Calcium and phosphorus metabolism in patients who have chronic kidney disease.
Disturbances in calcium and phosphorus metabolism are almost invariable consequences of chronic kidney disease (CKD). Because the capacity to regulate calcium and phosphorus metabolism becomes compromised progressively as kidney function declines, calcium and phosphorus homeostasis is disrupted and serum calcium or phosphorus levels are perturbed in many patients with CKD. The level of interest in, and concerns about, abnormalities in calcium and phosphorus metabolism among patients with CKD has increased substantially in recent years. Strategies for clinical management are being revised, and recent recommendations differ substantially from those used previously with a renewed emphasis on safety.
Calcium↗
Calcimimetics: a remedy for all problems of excess parathyroid hormone activity in chronic kidney disease?
PURPOSE OF REVIEW: Cinacalcet is a calcimimetic agent that is now available for use clinically to manage secondary hyperparathyroidism among patients undergoing dialysis regularly. It acts as an allosteric activator of the calcium-sensing receptor, the molecular mechanism that controls parathyroid hormone secretion. This mechanism of action differs fundamentally from that of the vitamin D sterols, which heretofore have been the only definitive pharmacological intervention for treating secondary hyperparathyroidism. RECENT FINDINGS: The ability of calcimimetic agents to enhance signaling through the calcium-sensing receptor in parathyroid cells affects several important components of parathyroid gland function. Results from several large clinical trials demonstrate that cinacalcet effectively lowers plasma parathyroid hormone levels in dialysis patients with secondary hyperparathyroidism when used either alone or together with vitamin D. Unlike the vitamin D sterols, which generally raise serum calcium and phosphorus levels, treatment with cinacalcet is associated with modest reductions in serum calcium and phosphorus concentrations. The impact of these biochemical changes on renal bone disease and on soft-tissue and vascular calcification during long-term treatment has yet to be characterized fully. Cinacalcet also diminishes parathyroid hormone gene expression, and studies in experimental animals indicate that its use retards the progression of parathyroid gland hyperplasia and increases bone mass. If confirmed in future clinical trials in patients with secondary hyperparathyroidism, these features represent potentially important ancillary therapeutic benefits. SUMMARY: Calcimimetic agents have diverse effects on parathyroid gland function that may enhance the overall medical management of secondary hyperparathyroidism in patients undergoing dialysis regularly.
Animals↗
Specific measurement of PTH (1-84) in various forms of renal osteodystrophy (ROD) as assessed by bone histomorphometry.
BACKGROUND: Parathyroid hormone (PTH) measurements serve as a noninvasive, diagnostic tool for the assessment of renal osteodystrophy (ROD). Their value has been questioned following reports indicating that all commercially available intact PTH (I-PTH) assays cross-react with amino terminally truncated PTH fragments. Because these fragments can account for 50% of total PTH, their detection will overestimate the true PTH concentration and may lead to diagnostic inaccuracies. The aim of this study was to evaluate the specific Bio-Intact PTH (1-84) Assay (BI-PTH) in patients with various types of ROD confirmed by bone biopsy. METHODS: Bone biopsies were taken from 132 patients with chronic kidney disease (CKD) stages 3 to 5, and quantitative bone histomorphometry was done. Plasma PTH levels were measured using both the BI-PTH and I-PTH assays on an automated analyzer. RESULTS: Patients with CKD stages 3/4 and low turnover skeletal lesions had BI-PTH values (pg/mL, mean +/- SD) of 35 (+/-34) and I-PTH values of 59 (+/- 63). Corresponding values for BI-PTH and I-PTH in those with high turnover lesions were 141 (+/-60) and 221 (+/-106). Patients with CKD stage 5 and low turnover skeletal lesions had BI-PTH and I-PTH levels of 51 (+/-38) and 90 (+/-60), respectively, whereas the corresponding results for BI-PTH and I-PTH in those with high turnover lesions were 237 (+/-214) and 461 (+/-437). The areas under the receiver operating characteristic (ROC) curves for distinguishing low turnover from high turnover lesions were 0.94 for BI-PTH and 0.91 for I-PTH in CKD stages 3/4 and 0.86 for BI-PTH and 0.85 for I-PTH in CKD stage 5. Among all patients, BI-PTH levels are approximately 50% lower than I-PTH levels, but the results of the two assays are correlated highly (R2 = 0.92). CONCLUSION: Plasma PTH measurements using either the BI-PTH or I-PTH assay effectively identify patients with reduced bone turnover and serve to distinguish this subgroup from those with high turnover lesions of renal bone disease. Both assays provide better diagnostic discrimination for this purpose than calculated values for the ratio of PTH (1-84)/amino terminally truncated PTH fragments.
Adult↗
First- and second-generation immunometric PTH assays during treatment of hyperparathyroidism with cinacalcet HCl.
BACKGROUND: First-generation immunometric assays for "intact" parathyroid hormone (iPTH) also measure large N-terminally truncated PTH fragments, whereas second-generation assays, such as the "bio-intact" PTH (biPTH) assay, measure only full-length biologically active PTH(1-84). This study compared iPTH and biPTH assays during cinacalcet treatment in subjects with secondary HPT receiving dialysis. METHODS: Four hundred and ten subjects were enrolled in a 26-week randomized, double-blind, placebo-controlled trial of oral cinacalcet (or placebo), 30 to 180 mg once daily, and efficacy was assessed using biPTH and iPTH assays. RESULTS: Compared with control treatment, cinacalcet improved the management of secondary HPT. Both biPTH and iPTH decreased by 38%+/- 3% during weeks 13 to 26 in the cinacalcet group; biPTH increased by 23%+/- 4% and iPTH increased by 9.5%+/- 3% in the control group (P < 0.001). Fifty-six percent of cinacalcet subjects and 10% of control subjects had a > or = 30% reduction in biPTH, and 61% and 11%, respectively, had a > or = 30% reduction in iPTH. Significant correlations between biPTH and iPTH levels were observed throughout the study. Both assays correlated similarly with bone-specific alkaline phosphatase levels. The ratio of biPTH to iPTH was maintained at 56% +/- 1% after treatment in both treatment groups. Increasing serum calcium levels were associated with a decreasing ratio of biPTH to (iPTH-biPTH). CONCLUSION: These data show that PTH can be monitored with either iPTH or biPTH assays during therapy with cinacalcet, and that cinacalcet therapy does not exert a major influence on the ratio between PTH(1-84) and large, N-terminally truncated PTH fragments.
Adult↗
Achieving NKF-K/DOQI bone metabolism and disease treatment goals with cinacalcet HCl.
BACKGROUND: The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-K/DOQItrade mark) has established guidelines for treatment of secondary hyperparathyroidism (HPT). The ability of cinacalcet HCl (Sensipartrade mark) treatment to improve achievement of target levels of parathyroid hormone (PTH), calcium, phosphorus, and calcium-phosphorus product (Ca x P) was investigated in subjects on dialysis with secondary HPT. METHODS: Data were combined from three placebo-controlled, double-blind, 26-week studies with similar design that randomized 1136 subjects on dialysis to receive traditional therapy plus cinacalcet or placebo. Oral cinacalcet was titrated from 30 to 180 mg/day. Achievement of K/DOQI goals was determined for each treatment group overall and for subgroups defined by baseline intact PTH (iPTH) and Ca x P levels. RESULTS: Cinacalcet-treated subjects were more likely to achieve a mean iPTH </=300 pg/mL (31.8 pmol/L) than were control subjects on traditional therapy (56% vs. 10%, P < 0.001). Cinacalcet-treated subjects were more likely to achieve concentrations of serum calcium within 8.4 to 9.5 mg/dL (2.10-2.37 mmol/L) and serum phosphorus within 3.5 to 5.5 mg/dL (1.13-1.78 mmol/L) than were control subjects (49% vs. 24% and 46% vs. 33%, P < 0.001 for each). Cinacalcet also improved achievement of Ca x P < 55 mg(2)/dL(2) (4.44 mmol(2)/L(2)) and concurrent achievement of Ca x P < 55 mg(2)/dL(2) (4.44 mmol(2)/L(2)) and iPTH </=300 pg/mL (31.8 pmol/L) (65% vs. 36% and 41% vs. 6%, P < 0.001 for each). CONCLUSION: In subjects on dialysis with secondary HPT, cinacalcet facilitates achievement of the K/DOQI-recommended targets for PTH, calcium, phosphorus, and Ca x P.
Adult↗
Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.
BACKGROUND: Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels. We report the results of two identical randomized, double-blind, placebo-controlled trials evaluating the safety and effectiveness of the calcimimetic agent cinacalcet hydrochloride. METHODS: Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less. The primary end point was the percentage of patients with values in this range during a 14-week efficacy-assessment phase. RESULTS: Forty-three percent of the cinacalcet group reached the primary end point, as compared with 5 percent of the placebo group (P<0.001). Overall, mean parathyroid hormone values decreased 43 percent in those receiving cinacalcet but increased 9 percent in the placebo group (P<0.001). The serum calcium-phosphorus product declined by 15 percent in the cinacalcet group and remained unchanged in the placebo group (P<0.001). Cinacalcet effectively reduced parathyroid hormone levels independently of disease severity or changes in vitamin D sterol dose. CONCLUSIONS: Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism.
Calcium↗
Bone histology in steroid-treated children with non-azotemic nephrotic syndrome.
Patients with nephrotic syndrome (NS) and normal glomerular filtration rate (GFR) frequently exhibit abnormalities of calcium and vitamin D homeostasis, mainly hypocalcemia and reduced circulating vitamin D metabolites. These abnormalities have been linked to alterations of bone histology in adults with non-azotemic NS, particularly osteomalacia and excessive bone resorption. Whether similar abnormalities of bone histology occur in children and adolescents with NS, particularly in those requiring prolonged treatment with corticosteroids, remains largely unknown. Thus, bone histomorphometry and selected bone-modulating hormones were studied in eight children (aged 2-16 years) with normal GFR (range 85-169 ml/min per 1.73 m(2)) and NS. All patients received corticosteroids for at least 12 months prior to bone biopsy. At the time of bone biopsy, the urine protein/creatinine ratio was elevated (2.1+/-3.6), while the average concentrations of parathyroid hormone (36+/-13 pg/ml), 25-hydroxyvitamin D [25(OH) D] (22+/-14 ng/ml), and 1,25(OH)(2)D (59+/-22 pg/ml) were normal. Bone histomorphometry displayed focal osteomalacia (OM) and mild increased bone resorption in most patients. The mineralization lag time, an indicator of the degree of osteomalacia, correlated with the time elapsed since the original diagnosis of NS ( r=0.93, P<0.0005). Overt hyperparathyroidism was not evident, but increased eroded perimeter and elevated bone formation rate (BFR) were evident in two patients, suggesting high-turnover bone disease. The BFR was inversely correlated with the administered dose of prednisone at the time of biopsy ( r=-0.78, P<0.05) and one patient exhibited low bone turnover changes. The growth velocity standard deviation score (SDS) at time of biopsy ranged from -1.6 to 3.2, resulting in a height SDS range of -1.9 to 0.6. The height SDS at time of bone biopsy correlated inversely with the dose of administered glucocorticoid ( r=-0.71, P<0.05) and with the duration of the disease ( r=-0.7, P=0.05). These data, albeit preliminary, demonstrate that children with NS treated with prolonged corticosteroid therapy exhibit bone histopathological changes without a concomitant impairment in GFR. While the OM appears to be related to the disease process, the alterations of bone formation and the adynamic changes are likely the result of the corticosteroid therapy. The potential consequences of these findings on adult bone mass and ultimate height deserve further studies.
Adolescent↗
Calcimimetic agents for the treatment of secondary hyperparathyroidism.
Calcimimetic agents function as allosteric activators of the calcium-sensing receptor (CaSR). In parathyroid tissue, they decrease the threshold for CaSR activation by extracellular calcium ions and diminish parathyroid hormone (PTH) secretion directly. Results from small clinical studies in hemodialysis patients with secondary hyperparathyroidism have shown that single oral doses of calcimimetic compounds abruptly decrease plasma PTH levels within 1 to 2 hours in a dose-dependent manner. Sustained decreases in plasma PTH levels can be achieved when daily oral doses are given for as long as 18 weeks. Decreases in plasma PTH levels often are associated with modest decreases in serum calcium and phosphorus levels, but symptomatic hypocalcemia is uncommon. Data gathered during larger more recent clinical trials lasting 12 to 24 months again indicate that plasma PTH levels can be decreased effectively with persistent and favorable decreases in serum phosphorus levels and in values for the calcium-phosphorus ion product in serum. Calcimimetic agents thus offer a novel treatment for secondary hyperparathyroidism in patients with chronic kidney disease stage 5, who are managed with dialysis. Unlike the vitamin D sterols, calcimimetic compounds effectively decrease plasma PTH levels without aggravating disturbances in mineral metabolism that have been associated with adverse clinical outcomes.
Aniline Compounds↗
Vascular calcification in chronic kidney disease.
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Arteriosclerosis↗
Calcium-sensing receptors.
It is now known that variations in extracellular calcium concentration exert diverse physiologic effects in a variety of tissues that are mediated by a calcium-sensing receptor (CaSRs). In parathyroid tissue, the CaSR represents the molecular mechanism by which parathyroid cells detect changes in blood ionized calcium concentration, modulate parathyroid hormone (PTH) secretion accordingly, and thus maintain serum calcium levels within a narrow physiologic range. In the kidney, the CaSR regulates renal calcium excretion and influences the transepithelial movement of water and other electrolytes. More generally, activation of the CaSR represents an important signal transduction pathway in intestine, placenta, brain, and perhaps bone. Some of these actions involve cell cycle regulation, changes that may be relevant to understanding the pathogenesis of parathyroid gland hyperplasia in secondary hyperparathyroidism caused by chronic kidney disease. The CaSR represents an appealing target for therapeutic agents designed to modify parathyroid gland function in vivo, offering the prospect of novel therapies for selected disorders of bone and mineral metabolism. Other receptors capable of responding to extracellular calcium ions also have been identified, but the functional importance of these interactions remains to be determined.
Calcium↗
Importance of hyperphosphataemia in the cardio-renal axis.
Hyperphosphataemia occurs in nearly all patients with end-stage renal disease (ESRD). In the past, the need to manage hyperphosphataemia focused primarily on its role as a contributor to secondary hyperparathyroidism and renal osteodystrophy. There is now widespread recognition that disturbances in phosphorus metabolism and/or the therapeutic measures used to manage it are important risk factors for cardiovascular calcification. This serious complication of chronic kidney disease may contribute to the very high mortality rate from cardiovascular causes in patients undergoing long-term dialysis. New strategies for controlling serum phosphorus levels and for better management of mineral metabolism in general are required to address these issues in patients with ESRD.
Animals↗
Medical control of secondary hyperparathyroidism: we're not there yet.
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Humans↗
The flavors of vitamin D: tasting the molecular mechanisms.
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Animals↗
Role of the calcium-sensing receptor in parathyroid gland physiology.
The calcium-sensing receptor (CaSR) represents the molecular mechanism by which parathyroid cells detect changes in blood ionized calcium concentration and modulate parathyroid hormone (PTH) secretion to maintain serum calcium levels within a narrow physiological range. Much has been learned in recent years about the diversity of signal transduction through the CaSR and the various factors that affect receptor expression. Beyond its classic role as a determinant of calcium-regulated PTH secretion, signaling through the CaSR also influences both gene transcription and cell proliferation in parathyroid cells. The CaSR thus serves a broad physiological role by integrating several distinct aspects of parathyroid gland function. The current review summarizes recent developments that enhance our understanding of the CaSR and its fundamental importance in parathyroid gland physiology.
Animals↗