Bone Markers and Bone Density Changes in Hyperperparathyroid Dialysis Patients Under Cinacalcet Treatment
Condition: Hyperparathyroidism; Secondary, Renal
MeSH terms: Hyperparathyroidism; Hyperparathyroidism, Secondary
Study type: Interventional

Summary: 
      Chronic kidney disease related mineral and bone disorders (CKD-MBDs) and secondary
      hyperparathyroidism (SHPT) are observed in most patients with chronic kidney disease on
      dialysis (CKD-5D). The original use of the calcimimetic cinacalcet in these patients was to
      reduce the elevated parathyroid hormone (PTH) levels; however, subsequent clinical studies
      consistently confirmed its beneficial effects on mineral disturbances and bone disease.
      Although many mechanisms proposed, its specific mechanisms underlying the bone disease is
      still unclear. Recently, Wnt signaling and their inhibitors were proposed to involve in fine
      control of osteoclast-to-osteoblast cross-talk. In previous study, investigators explore the
      changes in Wnt 10b in bone microenvironment after addition of calcimimetic cinacalcet using
      in vitro osteoclasts. In vitro results were confirmed in 5/6 nephrectomy mice, which were
      grouped into control, with cinacalcet and without cinacalcet groups. From in-vitro study,
      investigators found cinacalcet increase mineralization; enhance osteoclast apoptosis, which
      probably work as osteoclast-osteoblast cross talk for bone formation. Similar results were
      found in-vivo animal study, and the micro-CT of cinacalcet treated CKD animals revealed a
      significantly decrease in cortical porosity. On the basis of our in-vitro and animal study,
      investigators propose that cinacalcet have definitive role on bone turnover marker and bone
      density changes among SHPT dialysis patients.

      Methods: Our study includes 50 hyperparathyroid dialysis patients using cinacalcet from 1st
      Dec 2017 to 31 Oct 2018. Investigators will exclude post-menopausal female subjects.
      Enzyme-linked immunosorbent assay and Western blot analysis will be done for bone turnover
      markers (TRACP，Alk-P，S1P，BMP6，Wnt，10B，16，SOST，P1NP，PDGF BB，HGF and CTHRC1, etc.). Bone
      mineral density will be determined by dual-energy X-ray absorptiometry (DXA). Plasma
      fibroblast growth factor (FGF-23), Ca 2+ , P 3+ , calcium-phosphorus product and parathyroid
      hormone will also be measured. Data will be collected and analyzed the differences between
      baseline measures and 4 weekly and follow up for 6 months after the treatment. Control group
      that we enrolled 30 hyperparathyroid dialysis patients using traditional therapy active
      vitamin D without use cinacalcet.
    

Detailed description: 
      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.
    

Intervention name(s): Cinacalcet Tablets; calcitriol
Intervention type(s): Drug; Drug
Intervention description(s): All study subjects were treated with a fixed dose of oral Cinacalcet (25 mg/day) from baseline to 6 months.; All hyperparathyroidism were treated as traditional therapy with oral calcitriol 0.25 mcg(dosage according to IPTH serum level) from baseline to 6 months.
Other intervention name(s): CINACA®, Anxo, Taiwan; Macalol Cap 0.25mcg
Intervention MeSH terms: Calcitriol; Cinacalcet
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: clastokines; hemodialysis; hyperparathyroidism; osteoporosis