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

Abstract

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...

Diagnosis of renal osteodystrophy

“…It has been speculated that the reduced BMP-7 production in renal failure may contribute to the development of ABD [46] . This hypothesis is supported by experimental data by Lund and colleagues who reported an improvement of ABD in mice after BMP-7 treatment [23].…”

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

“…(15) Agents that enhance bone quality also reduce cardiovascular calcification. (16)(17)(18)(19)(20)(21)(22)(23) Additionally, soft-tissue calcification including vascular calcification is a common feature of genetic mouse and rat models harboring defects associated with bone mineralization. (24)(25)(26) Clinical improvements in bone health, regardless of the initial bone defect, ameliorate progression of cardiovascular disease.…”

Arterial stiffness, vascular calcification and bone metabolism in chronic kidney disease

“…Moreover, the skeletal remodeling disorders caused by CKD contribute directly to the disordered mineral metabolism and heterotopic mineralization, especially the VC in CKD [55] . Finally, CKD impairs skeletal anabolism, decreasing osteoblast function and bone formation [56] . Due to these pathophysiological discoveries, the term "CKD mineral bone disorder" (CKD-MBD) was created by the Kidney Disease Improving Global Outcomes Foundation (KDIGO) [57] .…”