Osteoporosis in Patients with Chronic Kidney Diseases: A Systemic Review

Abstract

Chronic kidney disease (CKD) is associated with the development of mineral bone disorder (MBD), osteoporosis, and fragility fractures. Among CKD patients, adynamic bone disease or low bone turnover is the most common type of renal osteodystrophy. The consequences of CKD-MBD include increased fracture risk, greater morbidity, and mortality. Thus, the goal is to prevent the occurrences of fractures by means of alleviating CKD-induced MBD and treating subsequent osteoporosis. Changes in mineral and humoral metabolism as well as bone structure develop early in the course of CKD. CKD-MBD includes abnormalities of calcium, phosphorus, PTH, and/or vitamin D; abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and/or vascular or other soft tissue calcification. In patients with CKD-MBD, using either DXA or FRAX to screen fracture risk should be considered. Biomarkers such as bALP and iPTH may assist to assess bone turnover. Before initiating an antiresorptive or anabolic agent to treat osteoporosis in CKD patients, lifestyle modifications, such as exercise, calcium, and vitamin D supplementation, smoking cessation, and avoidance of excessive alcohol intake are important. Managing hyperphosphatemia and SHPT are also crucial. Understanding the complex pathogenesis of CKD-MBD is crucial in improving one's short- and long-term outcomes. Treatment strategies for CKD-associated osteoporosis should be patient-centered to determine the type of renal osteodystrophy. This review focuses on the mechanism, evaluation and management of patients with CKD-MBD. However, further studies are needed to explore more details regarding the underlying pathophysiology and to assess the safety and efficacy of agents for treating CKD-MBD.

Keywords: chronic kidney disease; dialysis; fracture; osteoporosis.

Figure 1

A flowchart of article selection to illustrate the processes of database identification, article screening, consideration of eligibility and final inclusion according to the PRISMA statement.

Figure 2

A summary of the mechanism underlying the effects of chronic kidney disease (CKD) on osteoporosis and subsequent decrease in bone strength. (A) decrease clearance of FGF-23 [15,73,74]; (B) decrease phosphaturic effect of FGF-23 [75]; (C) inhibit 1α-hydroxylase in proximal tubule of kidney [20]; (D) increase renal tubular resorption of phosphate [76]; (E) induce hypocalcemia, decrease calcitriol, increase PTH gene expression and PTH secretion [20,33,77]; (F) decrease its inhibitory effect of due to decreased FGFR1 and kloth protein [78,79]; (G) inhibit 1α-hydroxylase [15]; (H) decrease intestinal absorption of Ca and decrease Ca release from bone [22,80]; (I) decrease number of VDRs in parathyroid cells [81] and decrease its inhibitory effect on parathyroid gland [20,82]; (J) increase PTH mRNA concentration [19,83] and decreased expression of the calcium-sensing receptor (CaSR) on parathyroid gland [27,84,85]; (K) Indoxyl sulfate decreases the expression of PTH1 receptor [21]; (L) the physicochemical precipitation of inorganic phosphate and calcium can indirectly give rise to skeletal resistance to PTH; (M) Indoxyl sulfate increases CpG hypermethylation of the Kloth gene [86]; (N) P-cresyl sulfate induces osteoblastic dysfunction [87].

Figure 3

Bone remodeling and effects of bisphosphonate, raloxifene, teriparatide, denosumab, and romosozumab on bone. Normally bone is continuously renewed through bone formation by osteoblasts and bone resorption by osteoclasts. Osteoblasts secret receptor activator of NF-κB ligand (RANK-L) and osteoprotegerin, which are main factors of bone remodeling. RANK-L stimulate the differentiation of osteoclast precusors and pre-osteoclasts through RANK-L and M-CSF receptors. Osteoprotegerin is a soluble combining inhibitor of RANK-L, which could reduce osteoclasts differentiation. Osteocytes secret sclerostin, which could reduce osteoblastogenesis and stimulate osteoclastogenesis by inducing RANK-L synthesis. Bisphosphonates have high affinity to hydroxyapatite and selectively inhibit farnesyl pyrophosphate synthase within osteoclasts and induce osteoclast apoptosis. Raloxifene is a selective estrogen receptor modulator and could enhance osteoclast apoptosis [119]. Intermittent administration of teriparatide could stimulate bone formation through the PTH-1 receptor expressed only in osteoblasts. Denosumab targets RANK-L, leading to suppression of osteoclasts differentiation. Romosozumab binds sclerostin, leading to both osteoblast activation and reduced osteoclastogenesis.