Bone Markers and Bone Density Changes in Hyperperparathyroid Dialysis Patients Under Cinacalcet Treatment

BACKGROUND Secondary hyperparathyroidism (SHPT) is an important mechanism underlying most cardiovascular and bone turnover disorders in CKD-5D patients, which contribute highest morbidity and mortality annually. Impair phosphate excretion and failure to bioactivate vitamin D during progressive renal function deterioration continuously stimulates the synthesis and secretion of parathyroid glands. Increase serum phosphate stimulates the phosphatonin fibroblast growth factor 23 (FGF-23) releases from osteocytes and osteoblasts. Elevated FGF-23 downregulates renal 25(OH)-1-hydroxylase which further deteriorates SHPT. Prolonged parathyroid gland functional activation leads to progressive parathyroid hyperplasia. Downregulation of the parathyroid vitamin D receptors and calcium-sensing receptors occurs within parathyroid gland, and principally responsible for the parathyroid hyperplasia. Hyperparathyroidism and alteration in mineral metabolism, especially hyperphosphatemia, modulate renal osteodystrophy and vascular calcification (together known as CKD-MBD). Continuously high PTH during SHPT stimulates osteoclastic resorption and bone remodeling rates, which leads to classic osteitis fibrosa. Excessive osteoblast viability and activity because of persistent hyperparathyroidism may follow to compensate for the bone resorption, with resultant osteosclerosis. Metastatic calcification and vascular calcification occur as a result of increased calcium and phosphate solubility product in extracellular fluid. The degree of mineralization is impaired in those with a high-turnover status because the recently formed bone is removed rapidly without adequate mineralization. Bones from a high-turnover state have lower mineralization and lower trabecular microhardness than do bones from normal or low-turnover states. A low mineral-to-matrix ratio and low carbonate-to-phosphate ratio reduce bone toughness. Moreover, collagen crosslinking abnormalities have been observed in both serum and soft tissue, which were responsible for bone quality in these patients. High PTH also generates microstructural damage at both the cortical and trabecular levels in CKD patients. Specifically, with chronic excess PTH secretion, increased catabolism and decreased cortical thickness is noted in cortical bone; whereas in trabecular bone, increased trabecular thickness with disturbed trabecular quality are noted. Taking together, SHPT patients have a higher risk of skeletal fractures and poor clinical outcomes associated with both bone quantity and quality loss.

Clinically, bone histomorphometry is still considered as the gold standard though clinically unfeasible due to its invasive and technician-dependent nature. Serum intact PTH (iPTH) and BSAP are recently used as markers of turnover to discriminate renal osteodystrophy. High serum iPTH and BSAP considered as high-turnover bone disease, whereas low serum iPTH, low BSAP, and normal vitamin D levels occur in adynamic bone disease (ABD) patients. Low vitamin D and PTH levels in conjunction with high levels of BSAP are correlated with osteomalacia. The Kidney Disease Outcomes Quality Initiative (K/DOQI) guideline use intact parathyroid hormone (iPTH) as a reliable surrogate marker for bone turnover and suggested that iPTH should be maintained in a target range between 150 and 300 pg ml-1 for patients with stage 5 CKD patients. However, some studies33 also found discrepancies between iPTH and histomorphometry findings in dialysis patients. Bone-derived markers of bone formation and resorption may be required to accurately measure bone structure and function in these patients. Bone formation markers including bone-specific alkaline phosphatase (BSAP), osteocalcin, and procollagen type-1 N-terminal propeptide (P1NP) are markers of osteoblast function. Bone resorption markers such as tartrate-resistant acid phosphatase 5b (Trap-5b) and C-terminal telopeptides of type I collagen (CTX) are markers of osteoclast number and function. Trap-5b and BSAP are not cleared by the kidneys and are mostly used in CKD patients as useful biomarkers. Osteocalcin, P1NP monomer, and CTX are cleared by the kidneys, and their usefulness in treating CKD patients remains unclear. Although many other circulating markers for bone remodeling disorders in CKD 34 patients have been evaluated, their clinical uses still not clear.

Human genetic studies have highlighted the crucial role of wingless (Wnt) signaling in bone mass regulation. Wnts are extracellular proteins that are linked to intracellular canonical and noncanonical Wnt signaling pathways when activated. They were found to be implicated in osteoblast and osteoclastic differentiation and function35, which are critical for trabecular and cortical bone mass. Wnt3a and Wnt10b, acting through canonical signaling; and Wnt16, acting through both canonical and noncanonical signaling, induce production of OPG in osteoblasts. OPG binds to the osteoclast-inducing cytokine RANKL and thereby inhibits osteoclast differentiation. Osteoblast Wnt5a potentiates RANK-induced osteoclast differentiation by activating ROR2-dependent noncanonical signaling. By contrast, Wnt 4 and Wnt 16 act directly through noncanonical signaling on osteoclast progenitors to inhibit RANKL-induced osteoclast formation. In addition to these known concepts about osteoblast-lineage cells influence on osteoclast precursors, recent researchers found that osteoclasts are capable of producing 'clastokines' that regulate osteoblast performance and bone formation. A study demonstrated that osteoclasts recruit osteoprogenitors and promote mineralization through the release of chemokine sphingosine 1 phosphate(S1P), bone morphogenetic protein 6 (BMP6) and Wnt10b. Further, osteoclast production of Wnt 10b found to mediate mineralization through increased TGF-βduring bone resorption phase. The sophisticated role of Wnt signaling in the human CKD and end-stage renal disease (ESRD) population still requires exploration. Several therapeutic interventions (active vitamin D analogues, phosphate binders, calcimimetics or surgical parathyroidectomy) are used nowadays to modulate mineral disturbances in order to reduce the CKD-MBD related clinical consequences. Calcimimetics, such as cinacalcet, a positive allosteric modulator of the calcium sensing receptor (CaSR), increases the PTH sensitivity to extracellular calcium and subsequently reduces the PTH secretion. Extensive preclinical studies have indicated that calcimimetics also arrest the progression of parathyroid hyperplasia. Combined randomized clinical trials (RCTs) and phase 4 studies confirmed the pleiotropic effects of calcimimetic agents in clinical grounds, including reduction of the elevated bone formation rate/tissue area with improvement in high turnover bone disorders. Some studies also confirm that adding calcimimetic cinacalcet can reduce the risk of fractures in SHPT patients. A bone histomorphologic study of 4 HD patients under cinacalcet treatment revealed decreased bone fibrosis, osteoblast surface and osteoid-related parameters.

Although mechanisms of calcimimetics in parathyroid hyperplasia are clearly explored, its effects on osteoclasts and osteoblasts (basic multicellular units) at bone remodeling sites are still unclear. A study revealed high extracellular calcium induces mitogenic action of osteoblasts via calcium-sensing receptors. However, another in vitro study on mouse and human adult osteoclastic and osteoblastic cells demonstrated the calcium dependent increase osteoblast formation and decrease osteoclast formation/function might not through the calcium sensing receptors, and not effected by calcimimetics. The calcimimetics might have any other mechanisms not through effects on calcium or calcium sensing receptors on these osteoblasts. Based on above information, investigators hypothesized that bone turnover markers including Wnt changes occur in SHPT hemodialysis patients. In addition, investigators consider the hypothetical role of cinacalcet mediated bone turnover changes occurred in the process of cinacalcet related bone anabolism.