An overview on adynamic bone disease clinical and therapeutical approaches

2014/2015 Mariana Barata Santos Barreira de Jesus An overview on adynamic bone disease clinical and therapeutical approaches março, 2015 Mestrado Integrado em Medicina Área: Nefrologia Tipologia:Monografia Trabalho efetuado sob a Orientação de: Doutor João Frazão Trabalho organizado de acordo com as normas da revista: Renal Failure Mariana Barata Santos Barreira de Jesus An overview on adynamic bone disease clinical an therapeutical approaches março, 2015 Aos meus pais e às minhas irmãs. State-of-the-Art-Review An overview on adynamic bone disease 1 An overview on adynamic bone disease clinical and therapeutical approaches M. Jesus 1 , João M. Frazão1, 2 1 School of Medicine of Porto University, Porto, Portugal 2 Nephrology Department, Centro Hospitalar de São João, EPE, Porto, Portugal and Nephrology and Infectiology Research and Development Group, INEB, Portugal Author data: Mariana Barata Santos Barreira de Jesus • Hospital de S. João, Serviço de Nefrologia, Alameda Hernâni Monteiro, 4200 Porto, Portugal • [email protected] • Fax: +351 228312529 Professor Doutor João Miguel Machado Dória Frazão • Hospital de S. João, Serviço de Nefrologia, Alameda Hernâni Monteiro, 4200 Porto, Portugal • [email protected] • Fax: +351 228312529 Corresponding author: Professor Doutor João M. Frazão • Serviço de Nefrologia, Alameda Hernâni Monteiro, 4200 Porto, Portugal • [email protected] State-of-the-Art-Review An overview on adynamic bone disease 2 Key Words: adynamic bone disease; chronic kidney disease; mineral and bone disorder; vascular calcification; low calcium dialysate; non-calcium containing phosphate binders. State-of-the-Art-Review An overview on adynamic bone disease 3 Abstract Adynamic Bone disease is a bone and mineral disorder that reflects abnormalities in calcium homeostasis with low calcium buffer capacity and inability to handle this ion’s extra load. Its prevalence has been rising in the latest two decades as a result of generalized use of calcium-containing phosphate binders combined with vitamin D receptor agonists. The association between Adynamic Bone Disease and diabetes mellitus, as well as peritoneal dialysis, the Wnt signaling inhibitor sclerostin and the malnutrition-inflammation complex reflects the unknown multifactorial causes that lead to this disease. The gold-standard method for the diagnosis of Adynamic Bone Disease is bone biopsy with tetracycline labeling, however, this is an invasive, expensive method that is not widely available, and so, biochemical markers, such as serum Parathyroid Hormone are used to make the diagnosis, even though they cannot fully replace bone biopsy. One of the greatest burdens of Chronic Kidney Disease is vascular calcification. This active process leads to arterial stiffening and to higher cardiovascular and noncardiovascular mortality rates. Interestingly, lower levels of Parathyroid Hormone, as seen in patients with Adynamic Bone Disease, are associated with higher mortality rates than higher levels. The objectives of the treatment of this disorder are mainly to prevent the excessive calcium load, using lower calcium dialysate, non-calcium-containing phosphate binders and avoiding Vitamin D therapy. Some novel therapies are being tested, such as Teriparatide and Menatetrenone, but no definite conclusions can be taken at this moment on the effect of these agents. State-of-the-Art-Review An overview on adynamic bone disease 4 Introduction Chronic Kidney Disease (CKD) is an global public health problem affecting 5-10% of the world population 1. As the kidney function declines there is a deterioration of the mineral homeostasis with altered serum and tissue concentration of phosphorus and calcium as well as changes in circulating levels of hormones. In the course of CKD there is a reduction in the ability of the kidney to excrete an adequate load of phosphate which leads to hyperphosphatemia, elevation of parathyroid hormone (PTH) and FGF-23. The conversion of 25(OH)D to 1,25(OH)D is impaired, stimulating PTH secretion. The kidney also fails to respond adequately to PTH (that increases calcium reabsorption and promotes phosphaturia) and to FGF-23 (that increases phosphaturia). As this functions are of crucial importance to the metabolism of bone is not surprising that bone anomalies are present in virtually every patient with CKD stage 5D (requiring dialysis) and in the majority of patients in stage 3-5 1. Recently, more importance as been given to the canonical wnt signaling. Wnt ligands bind to the LRP5/6 membrane receptor complex increasing bone formation. Sclerostin is a wnt signaling inhibitor, decreasing bone formation and osteoblast activity 2. A cross-sectional study, showed higher levels of serum sclerostin in patients with stage 5 CKD when compared to no CKD controls. This might be due to an increased retention or production 3. In this study only sclerostin was associated with bone turn-over, pointing to a superior value of this parameter as a noninvasive indicator of bone turn-over. However, this superiority was only observed in high turn-over bone disease. A recent cross-sectional study evaluated serum and trabecular bone surface sclerostin in peritoneal dialysis patients showing that, not only were both parameters elevated in these patients, but they were also negatively associated to bone alkaline phosphatase and bone formation rate 2. When serum and trabecular bone State-of-the-Art-Review An overview on adynamic bone disease 11 Diagnosis of adynamic bone disease The definitive diagnosis of renal osteodystrophy, requires a bone biopsy 1. This is done by the histomorphometric analysis of an undecalcified bone sample that requires a prebiopsy tetracycline labelling as well as aluminum and amyloid stains for a complete workup. In order to correctly diagnosis and differentiate the different types of renal osteodystrophy assessment of bone turn-over, mineralization and fibrosis are required 11. However, in clinical practice, this can’t always be done because it is an invasive, time consuming, and expensive procedure not widely available 5. Considering this, biochemical abnormalities are the most commonly used indicators by which the diagnosis of MBD is made 1 even with the knowledge that none of the biochemical markers for bone reabsorption, formation or parathyroid status are accurate enough to replace the bone biopsy 11. According to the Kidney Disease Outcomes Quality Initiative, in patients with CKD stage 5, PTH concentration should be measured regularly and maintained within 150-300 pg/ml. However, Barreto et al showed that even within the target range (150-300 pg/ml) the most common finding on bone biopsy was low turn-over (n=22, 63,6%) and that only a small number of patients in this range presented with normal bone turn-over (n=22, 9%) 22. A study with overlapping results was performed in Portugal by Ferreira et al in which a prevalence of ABD of 59% with PTH levels within KIDIGO target range is reported 8. The first generation of PTH assays were radioimmunoassays which measured not only the PTH 1-84 molecule but also its fragments produced in the liver and eliminated by the kidney that accumulate in patients with CKD, producing highly increased levels of PTH and with poor sensitivity for low PTH concentration 23. These assays are considered obsolete in the present day. Serum PTH is a combination of PTH1-84, the full hormone, State-of-the-Art-Review An overview on adynamic bone disease 12 as well as its carboxy-terminal fragments 24. The most important of this fragments is PTH7-84, which is also detected by the second generation PTH assays, the intact PTH assays 25. More recently, the third generation assays, the whole PTH assays, where developed. Using an N-terminal antibody directed against the first amino-acids this assay does not measure the PTH 7-84 23. Therefore, the difference between the values measured with the intact PTH assay and the whole PTH assay represents the PTH 7-84 concentration. It has been demonstrated that PTH 7-84 antagonizes the calcemic response to PTH 184, probably modulating the effects of PTH 1-84 on bone 25. This antagonizing effect was explored Mauniere-Faugere et al in a study that proposes the use of the PTH 1-84/PTH Carboxy terminal fragments ratio as a method of predicting bone turn-over 26. The study showed the superiority of this ration in predicting bone turn-over when compared to all other biochemical markers, alone or in combination. Predominance of the active PTH 184 form is associated with high bone turn-over and predominance of the PTH Carboxyl terminal fragments is associated with low bone turn-over. However, this superiority was not confirmed in a more recent report 27. Both the second and third generation assays are used in the clinical practice introducing a great inter-method variability. The intra-method variability also represents a problem and its due to the lack of standardization and antibody specificity25. Bone alkaline phosphatase is a fraction of the serum alkaline phosphatase produced by the osteoblasts. It is very important marker of bone formation and its elevated levels virtually exclude the presence of ABD 7. A recent study with 41 peritoneal dialysis patients demonstrated that bone alkaline phosphatase was, not only, a good marker for bone turn-over, but a slight superiority of bone alkaline phosphatase was found when State-of-the-Art-Review An overview on adynamic bone disease 13 compared to intact PTH 2. This biochemical parameter is particularly useful in patients with liver disease. Serum PTH values below 100pg/ml or above 800pg/ml have a good diagnostic value for ABD and high turn-over disease, respectively. Is in the patients presenting with serum PTH levels between 100pg/ml and 500pg/ml that lays the greater difficulty in reaching a satisfying diagnosis without performing a bone biopsy 7. State-of-the-Art-Review An overview on adynamic bone disease 14 Clinical presentation of adynamic bone disease Bone Fractures Due to the impaired bone remodeling process, patients with ABD have poorer repair of microfractures. This leads to more frequent episodes of fractures 28. A study by Atsumi et al that evaluated compression vertebral fractures in hemodialysis patients showed that the subgroup with the lowest percentile of PTH had the highest risk of these fractures 29. Another study, by Coco et al, presented similar results with hip fractures, with patients with the lower PTH levels being more likely to sustain hip fractures than the ones with higher PTH levels 30. In both studies, patients with CKD presented with significantly higher fracture risk than the patients without CKD. Cardiovascular calcification Cardiovascular calcifications represent an important problem in patients with End Stage Renal Disease 11. Besides common atherosclerosis with patchy calcification of atherosclerotic plaques, hemodialysis patients also present mediasclerosis 31. The second one seems to be related to mineral disturbances associated with CKD and represents an active process in which vascular muscle cells differentiate into osteoblasts as a response to stimuli such as hyperphosphatemia 31. To establish the influence of hyperphosphatemia and its mechanisms in vascular calcification a human aortic muscle cell culture was exposed to phosphate levels comparable to those found in hyperphosphatemic patients and a dose-dependent increase in cell culture calcium deposition was showed. Also, when exposed to these levels of phosphate, an enhanced expression of osteocalcin and Cbfa-1, known osteogenic markers, was shown. These changes were mediated by a sodium-dependent phosphate cotransporter (NPC)31. These findings reveal the active nature of this process, but, such as this one, there are State-of-the-Art-Review An overview on adynamic bone disease 15 probably more pathways involved in vascular calcification, and for this reason the continuing search on this area is of great importance. Cardiovascular calcification represents an important problem due to its impact in mortality and morbidity. Coronary artery calcification progression was associated with progressive deterioration of arterial stiffness and cardiac repolarization 32. Another study reported that the presence of arterial calcifications in end stage renal disease is highly predictive of all-cause mortality and cardiovascular mortality and also that arterial media calcifications represent an independent prognostic marker for all-cause mortality as well as cardiovascular mortality in hemodialysis patients 33. A simple vascular calcification score based on plane radiographic films of the pelvis and hands has shown to be a simple tool useful to the assessment of cardiovascular risk related to vascular calcification in hemodialysis patients 34. A score of 3 or higher was independently associated with peripheral artery disease, coronary artery disease and vascular disease. These patients also presented a 3.9 fold increase risk of cardiovascular mortality, a 2.9 fold increase in cardiovascular hospitalizations as well as a 2.4 fold increase in the risk of fatal and nonfatal cardiovascular events. The association between cardiovascular calcification and low bone turn-over has been described by several authors. A study, published in 2004 by London et al, compared bone histomorphometric characteristics with the arterial calcification scores (0 to 4) which were determined through the number of sites with arterial calcifications using ultrasound evaluation. The study showed that patients with highest arterial calcifications scores (3 and 4) had lower PTH levels, lower osteoclast numbers and osteoblastic surfaces, smaller or absent double tetracycline-labeled surfaces as well as higher percentages of aluminum stain surfaces, which reveals an association between high arterial calcification and low bone activity and ABD. The data analysis concluded that arterial calcification had an inverse correlation with osteoblastic surfaces. Later, in 2008, the same author State-of-the-Art-Review An overview on adynamic bone disease 16 conducted a study to evaluate the interaction between bone activity, assessed by histomorphometric analysis, and the use of calcium-containing phosphate binders with the extent of abdominal aortic calcification and aortic stiffness, assessed by pulse wave velocity, in hemodialysis patients 35. In this study, not only biopsy proven ABD was associated with greater aortic stiffness independently of any other factor, but also, patients with ABD showed stronger association between calcium load and aortic calcification score and aortic stiffness. This indicates that the presence of ABD disease conferred a greater influence of calcium load to both aortic calcification and stiffening. A cohort study nested within a randomized controlled trial was performed to evaluate the association between bone remodeling disorders and progression of vascular calcification, more specifically, coronary artery calcification 36. Biochemcial parameters of bone activity were evaluated throughout the study and bone histomorphometry was assessed at baseline and after 1 year of follow-up. Coronary artery calcification was assessed by coronary multislice tomography at baseline and after 1 year of follow-up, with a score of 30 Agatston units of greater at baseline representing calcification and a change in the score of 15% or greater representing progression. Patients with a biopsy proven low turn-over disease at baseline who showed higher bone formation rate and osteoid volume at follow-up were associated with lower coronary artery calcification progression. Also, patients with lesser coronary artery calcification progression presented greater levels of bone specific alkaline phosphatase at follow-up. Low bone turn-over status was the only independent predictor of coronary artery calcification progression at the 12-month bone biopsy. A more recent study, involving 207 CKD stage 5 patients, evaluated the association between bone turn-over, assessed by histomorphometric analysis, and coronary artery calcification, measured using multi-slice computed tomography 37. A negative association between activation frequency and coronary artery calcification score and State-of-the-Art-Review An overview on adynamic bone disease 17 bone formation rate/bone surface and coronary artery calcification scores was found in patients with low turn-over. The recent recognition of the Wnt signal inhibitor sclerostin as an important regulator of bone metabolism has led to its study as a mediator in vascular calcification and it has already been shown that sclerostin is expressed in calcifying vasculature 38. A 2013 posthoc survival analysis showed that hemodialysis patients with levels of sclerostin above median, after adjustment for age and gender, had a significant greater survival 39. The authors explain this finding through the pre-existing hypothesis that the expression of wnt signaling inhibitors in calcifying vascular tissue may be a defensive response to limit the ossification and therefore limit the progression of the vascular calcification. Interestingly, a 2014 study with a cohort of 91 patients followed during a ten-year period showed that high sclerostin was associated with cardiovascular mortality, independently from diabetes and age 40. Some reasons for this discrepancy were postulated by the authors, including the younger cohort and lesser percentage of diabetic patients, as well as the adjustment for diabetes in the more recent study. These inconsistencies in the results reveal a need for further investigation on this matter, ideally with large scale studies. State-of-the-Art-Review An overview on adynamic bone disease 18 Therapeutic approaches to adynamic bone disease Low calcium dialysate and calcium profiling Numerous investigators have suggested the use of low calcium dialysate in hemodialysis patients as a way to lower the risk of hypercalcaemia and excessive PTH suppression. A 6 months study with 60 patients with pre dialysis intact PTH<100 pg/ml equally distributed over low dialysate calcium (1.25mmol/l) and high dialysate calcium (1.75mmol/l) explored this hypothesis 41. The mean of total and ionized calcium was markedly increased in the high calcium dialysate at the end of dialysis. This was not observed in the low calcium dialysate group, where there were no differences in these parameters at baseline and end of dialysis. As expected, total and ionized calcium were significantly higher in the high calcium dialysate group when compared to the low calcium dialysate group throughout the study. Intact PTH, total alkaline phosphatase and bone alkaline phosphatase increased from baseline in the low calcium dialysate group. Moreover, all parameters reached higher levels in the low calcium dialysate when compared with the high calcium dialysate. These results suggest a benefic effect of low calcium dialysate on improving adynamic bone. A prospective trial involved 425 hemodialysis patients who with a follow up of 24 months explored the effects of lowering the calcium dialysate in bone histomorphometry and in the progression of the coronary artery calcification score 42. All patients had a PTH<300pg/ml and prior treatment with 1.5ml/L calcium dialysate. Patients receiving treatment with vitamin D in the preceding six months were excluded. Patients were randomized in to either 1.25ml/L or 1.75ml/L dialysate calcium. Bone biopsy was performed at baseline and after 24 months of follow-up. Bone histomorphometric analysis showed that bone formation rate, osteoblast surface/bone surface ratio as well as bone volume/tissue volume ratio increased in the group with the lowest calcium State-of-the-Art-Review An overview on adynamic bone disease 19 dialysate, but not in the one with the highest. PTH levels were also significantly higher in the low calcium dialysate patients. These findings showed an improvement in bone formation and in bone turnover with the use of low calcium dialysate hemodialysis leading to an improvement of adynamic bone disease. Moreover, coronary artery calcification progression was significantly less pronounced in the group with the low calcium dialysate. Similar results regarding bone formation rate and PTH had already been reported in 2006 28, however the great strength of this more recent study is the large number of patients enrolled and evaluated. Low calcium dialysate is, however, associated with some harmful effects such as hemodynamic instability and cardiac rhythm disturbances. Calcium profiling with a profiled dialysate calcium concentration from 1.63mM/l at the beginning of the session to 1.93mM/l at the end was assessed in a multicenter, prospective, randomized trial 43. Patients in the calcium profiling group were compared with patients treated with low calcium dialysate (1.25mM/l) and with high calcium dialysate (2mM/l). Total amount of calcium given to the patient in the profiling group was higher than in the low calcium dialysate group, but lower than in the high calcium dialysate group. This higher amount of calcium was contra balanced by the absence of the systolic and diastolic arterial pressure decrease seen in the low calcium dialysate group. This results show that calcium profiling in hemofiltration is a way to guarantee cardiovascular stability during the hemodialysis session while reducing the risk of calcium overload. More studies need to be done to assess the effects of calcium profiling in bone parameters and, if possible, in bone histomorphometry. State-of-the-Art-Review An overview on adynamic bone disease 20 Non-calcium phosphate binders Although used widely to maintain the serum phosphate within the target values, calciumcontaining phosphate binders are associated with a positive calcium balance, hypercalcaemia, parathyroid gland suppression, ABD and coronary and aortic calcification 44. With the advent of the non-calcium phosphate binders their effect on mortality, bone histology, vascular calcification, safety and effectiveness has been evaluated. Sevelamer hydrochloride Sevelamer hydrochloride is an aluminum and calcium free, non-absorbed polymer, with no potential for systemic accumulation. In a multicenter, prospective, randomized, noblinded study, 212 patients were randomized to either sevelamer hydrochloride or calcium carbonate 45. Sevelamer treated patients presented with significantly lower final and on-treatment phosphorus levels, although the proportion of patients on CKD stagespecific target of serum phosphorus was identical between the two groups. Sevelamer treated patients also presented a better PTH control and a final and on-treatment decreased serum calcium concentration. Adding to this, final and on-treatment average total cholesterol and LDL-cholesterol were significantly reduced in the sevelamer group. In this study the rate of all cause mortality, dialysis inception and the composite endpoint (all cause mortality and dialysis inception) was also significantly less frequent in the sevelamer treated patients. Other studies have also showed a decrease in mortality with sevelamer compared with calcium carbonate, although without statistical significance 46. A randomized clinical trial comparing sevelamer with calcium based phosphate binders in 200 hemodialysis patients aimed to compare the calcification of the coronary and aortic arteries 47.This study showed that the medium absolute calcium score increased significantly in the calcium treated group, but not in the sevelamer group (coronary State-of-the-Art-Review An overview on adynamic bone disease 27 Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. State-of-the-Art-Review An overview on adynamic bone disease 28 References 1. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney international. Supplement. 2009(113):S1-130. 2. de Oliveira RA, Barreto FC, Mendes M, et al. Peritoneal dialysis per se is a risk factor for sclerostin-associated adynamic bone disease. 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Anti-Sclerostin Antibody Treatment in a Rat Model of Progressive Renal Osteodystrophy. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2014. ANEXOS !