A novel mechanism for skeletal resistance in uremia

Slatopolsky, Eduardo; Finch, Jane; Clay, Patricia; Martin, Daniel R.; Sicard, Gregorio; Singer, Gary G.; Gao, Ping; Cantor, Thomas L.; Dusso, Adriana

doi:10.1016/s0085-2538(15)47156-x

Cited by 377 publications

(302 citation statements)

References 26 publications

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“…Most commercial intact parathyroid hormone (intact PTH) assays cross-react with non-(1-84) PTH (likely 7-84 PTH). The 7-84 PTH showed inversed biological activity to 1-84 PTH resulting in hypocalcemia [19]. A higher ratio of 7-84 PTH to intact PTH or 1-84 PTH (whole PTH) may explain the results of high PTH levels with mild hypercalcemia in parathyroid cancer patients.…”

Section: Resultsmentioning

confidence: 98%

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Parathyroid carcinoma: a 16-year experience in a single institution

et al. 2010

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Section: Resultsmentioning

confidence: 98%

“…Postoperative serum calcium concentrations should be monitored closely because patients may experience hungry bone syndrome which results in symptomatic hypocalcemia from calcium and phosphorous deposition into the bones, and calcium and calcitriol medication might be required [19].…”

Section: Discussionmentioning

confidence: 99%

Parathyroid carcinoma: a 16-year experience in a single institution

et al. 2010

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“…The increased serum OPG concentrations in patients with chronic kidney disease may be an adaptive mechanism to attenuate PTH-induced bone loss (Kazama et al 2002). The sensitivity of PTH to bone differs among dialysis patients (Andress et al 1987;Slatopolsky et al 2000;Iwasaki et al 2006). Thus, the relationship between PTH and OPG may also differ among these patients.…”

Section: Discussionmentioning

confidence: 99%

Association between Increased Serum Osteoprotegerin Levels and Improvement in Bone Mineral Density after Parathyroidectomy in Hemodialysis Patients

Zheng

Chu

et al. 2012

Tohoku J. Exp. Med.

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Secondary hyperparathyroidism (SHPT) is a common complication in chronic renal disease. Osteoprotegerin (OPG), an extracellular cytokine receptor secreted by osteoblasts, can promote bone formation by inhibiting the function of osteoclasts. Hemodialysis (HD) patients have elevated serum OPG levels. OPG secretion can be suppressed with high parathyroid hormone (PTH) levels. HD patients with refractory SHPT can benefit from parathyroidectomy (PTX) treatment, but the changes of serum OPG, bone turnover markers and bone mineral density (BMD) following PTX in HD patients remain unclear. In this study, patients on maintenance HD who received PTX for refractory SHPT (n = 28) were prospectively followed for 1 year. Serum intact PTH (iPTH), alkaline phosphatase (Alk-P), and OPG were measured serially; BMD was measured pre-PTX and at 1 year after PTX. After PTX, serum iPTH levels reduced profoundly. Serum Alk-P levels increased rapidly, peaking at 2 weeks post-PTX, while serum OPG levels gradually increased at 2 weeks after PTX and peaked at 2 months. BMD improved in both femoral neck (FN; cancellous and cortical bone) and lumbar spine (LS; cancellous bone). Higher baseline iPTH levels were associated with greater FN and LS BMD improvements at one year after PTX. The increment of serum OPG was correlated with the increase in LS BMD, implying that inhibition of osteoclastic bone resorption may improve BMD within the first year after PTX. These findings suggest that PTX removes the suppressive effects of high PTH on OPG secretion, resulting in the increased serum OPG levels that may contribute to BMD improvement.

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“…Because secondary hyperparathyroidism in CKD causes a distinct osteodystrophy, increasing PTH levels to increase bone remodeling cannot be considered adequate therapy for the ABD. The skeleton is resistant to the actions of PTH during CKD (13,14). Many potential mechanisms of skeletal resistance to PTH have been proposed (13,15).…”

mentioning

confidence: 99%

“…The skeleton is resistant to the actions of PTH during CKD (13,14). Many potential mechanisms of skeletal resistance to PTH have been proposed (13,15). One, which has not been tested, is that CKD directly decreases skeletal anabolic activity.…”

mentioning

confidence: 99%

Successful Treatment of an Adynamic Bone Disorder with Bone Morphogenetic Protein-7 in a Renal Ablation Model

Lund¹,

Davies²,

Brown³

et al. 2004

Journal of the American Society of Nephrology

103

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Abstract. An adynamic bone disorder (ABD) is an important complication of chronic kidney disease (CKD) of unknown etiology for which there is no adequate treatment. Reported is an animal model of ablative CKD complicated by an ABD characterized by the absence of secondary hyperparathyroidism and its successful treatment with a skeletal anabolic factor, bone morphogenetic protein-7 (BMP-7). Adult mice were subjected to electrocautery of the right kidney followed by left nephrectomy. Animals were randomized into groups fed normal chow or fed low-phosphate chow supplemented with calcitriol to maintain normophosphatemia in CKD. All groups were maintained on the regimens for 12 wk. Hyperphosphatemia, secondary hyperparathyroidism, and a mild osteodystrophy developed in the CKD/chow-fed group, as expected. When dietary phosphorus was restricted and calcitriol was administered in the CKD low-phosphate/calcitriol group (ABD), Ca, PO 4 , and parathyroid hormone levels were maintained normal. A significant ABD developed in the ABD group characterized by significant depressions in osteoblast number, perimeters, bone formation rates, and mineral apposition rates when compared with the sham-operated, chow-fed group. The abnormal skeletal histomorphometry was reversed by BMP-7 therapy to normal values and significantly improved from the ABD group (P Ͻ 0.05). The sham-operated low-phosphate/ calcitriol-fed control group and the CKD low-phosphate/calcitriol/BMP-7 groups had reduced phosphate levels compared with the other groups (P Ͻ 0.05). ABD produced in mice with CKD in the absence of hyperparathyroidism was successfully reversed with a bone anabolic, BMP-7, associated with a reduction in plasma phosphorus.Renal osteodystrophy is a term used to describe a heterogeneous spectrum of skeletal abnormalities found in patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD). Renal osteodystrophy ranges from states of high bone turnover to states of low bone turnover (1-3). Predominantly hyperparathyroid bone disease results in a high turnover osteodystrophy (osteitis fibrosa), and it is considered the most prevalent bone disorder in chronic kidney disease and ESKD. Low-turnover osteodystrophy reflects the lack of capacity to produce and mineralize bone matrix and has two main histologic forms: osteomalacia and the adynamic bone disorder (ABD). The ABD is an important complication of CKD associated with high rates of bone fractures (4), impaired growth (5,6), and probably vascular calcification (7,8). There has been an increase in the prevalence of ABD in patients with ESKD on dialysis (9).The pathogenesis of the ABD is unknown. It may occur when parathyroid hormone (PTH) levels are aggressively suppressed (10). As a result, practice standards target maintaining elevated intact PTH levels (about three to five times normal) sufficient to prevent the ABD (11,12). Therapy of the ABD besides adjustment of PTH levels is not available. Because secondary hyperparathyroidism in CKD causes a distinct osteodystrophy, in...

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A novel mechanism for skeletal resistance in uremia

Cited by 377 publications

References 26 publications

Parathyroid carcinoma: a 16-year experience in a single institution

Parathyroid carcinoma: a 16-year experience in a single institution

Association between Increased Serum Osteoprotegerin Levels and Improvement in Bone Mineral Density after Parathyroidectomy in Hemodialysis Patients

Successful Treatment of an Adynamic Bone Disorder with Bone Morphogenetic Protein-7 in a Renal Ablation Model

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