Bone histomorphometry before and after long-term treatment with cinacalcet in dialysis patients with secondary hyperparathyroidism
2014; Elsevier BV; Volume: 87; Issue: 4 Linguagem: Inglês
10.1038/ki.2014.349
ISSN1523-1755
AutoresGeert J. Behets, Goce Spasovski, Lulu Ren Sterling, William G. Goodman, David M. Spiegel, Marc E. De Broe, Patrick C. D’Haese,
Tópico(s)Vitamin D Research Studies
ResumoThe multicenter, single-arm BONAFIDE study characterized the skeletal response to cinacalcet in adult dialysis patients with plasma parathyroid hormone (PTH) levels of 300pg/ml or more, serum calcium of 8.4mg/dl or more, bone-specific alkaline phosphatase over 20.9ng/ml and biopsy-proven high-turnover bone disease. Of 110 enrolled patients, 77 underwent a second bone biopsy with quantitative histomorphometry after 6–12 months of cinacalcet treatment. The median PTH decreased from 985pg/ml at baseline to 480pg/ml at the end of study (weeks 44–52). Bone formation rate/tissue area decreased from 728 to 336μm2/mm2/day, osteoblast perimeter/osteoid perimeter decreased from 17.4 to 13.9%, and eroded perimeter/bone perimeter decreased from 12.7 to 8.3%. The number of patients with normal bone histology increased from none at baseline to 20 at 12 months. Two patients had adynamic bone at the end of study with a PTH under 150pg/ml, and one patient with overt hypophosphatemia at baseline that reoccurred during follow-up developed osteomalacia. Thus, long-term treatment with cinacalcet substantially reduced PTH, diminished the elevated bone formation rate/tissue area, lowered several biochemical markers of high-turnover bone disease toward normal, and generally improved bone histology. Twenty patients had normal bone histology at follow-up, whereas most had mild hyperparathyroidism or mixed uremic osteodystrophy. The multicenter, single-arm BONAFIDE study characterized the skeletal response to cinacalcet in adult dialysis patients with plasma parathyroid hormone (PTH) levels of 300pg/ml or more, serum calcium of 8.4mg/dl or more, bone-specific alkaline phosphatase over 20.9ng/ml and biopsy-proven high-turnover bone disease. Of 110 enrolled patients, 77 underwent a second bone biopsy with quantitative histomorphometry after 6–12 months of cinacalcet treatment. The median PTH decreased from 985pg/ml at baseline to 480pg/ml at the end of study (weeks 44–52). Bone formation rate/tissue area decreased from 728 to 336μm2/mm2/day, osteoblast perimeter/osteoid perimeter decreased from 17.4 to 13.9%, and eroded perimeter/bone perimeter decreased from 12.7 to 8.3%. The number of patients with normal bone histology increased from none at baseline to 20 at 12 months. Two patients had adynamic bone at the end of study with a PTH under 150pg/ml, and one patient with overt hypophosphatemia at baseline that reoccurred during follow-up developed osteomalacia. Thus, long-term treatment with cinacalcet substantially reduced PTH, diminished the elevated bone formation rate/tissue area, lowered several biochemical markers of high-turnover bone disease toward normal, and generally improved bone histology. Twenty patients had normal bone histology at follow-up, whereas most had mild hyperparathyroidism or mixed uremic osteodystrophy. Bone disease is a major consequence of secondary hyperparathyroidism (sHPT) among patients with chronic kidney disease (CKD). It is an integral component of the syndrome of CKD–mineral and bone disorder affecting a substantial proportion of patients undergoing dialysis. The skeletal manifestations of sHPT arise largely from the ongoing release of excess amounts of parathyroid hormone (PTH) into the circulation by enlarged parathyroid glands.1.Cunningham J. Locatelli F. Rodriguez M. Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options.Clin J Am Soc Nephrol. 2011; 6: 913-921Crossref PubMed Scopus (380) Google Scholar Accordingly, serum or plasma PTH levels are elevated, often markedly so. A key objective in the treatment of sHPT is to lower PTH levels toward recommended target ranges and to correct the histopathological changes of sHPT in bone.2.Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work Group KDIGO Clinical practice guidelines for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease—mineral and bone disorder (CKD-MBD).Kidney Int. 2009; 76: S1-S130Google Scholar Vitamin D sterols and calcimimetic agents are the only two pharmacological interventions available currently to lower PTH levels among patients with sHPT managed with dialysis. Treatment with vitamin D sterols has been shown to reduce PTH, mostly in small studies lasting several weeks or only a few months.3.Quarles L.D. Role of FGF23 in vitamin D and phosphate metabolism: implications in chronic kidney disease.Exp Cell Res. 2012; 318: 1040-1048Crossref PubMed Scopus (199) Google Scholar,4.Moe S.M. Saifullah A. LaClair R.E. et al.A randomized trial of cholecalciferol versus doxercalciferol for lowering parathyroid hormone in chronic kidney disease.Clin J Am Soc Nephrol. 2010; 5: 299-306Crossref PubMed Scopus (68) Google Scholar The PTH-lowering effect of the calcimimetic agent cinacalcet (Sensipar/Mimpara) is recognized generally,5.Goodman W.G. Hladik G.A. Turner S.A. et al.The calcimimetic agent AMG 073 lowers plasma parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism.J Am Soc Nephrol. 2002; 13: 1017-1024PubMed Google Scholar, 6.Block G.A. Martin K.J. de Francisco A.L. et al.Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.N Engl J Med. 2004; 350: 1516-1525Crossref PubMed Scopus (950) Google Scholar, 7.Raggi P. Chertow G.M. Torres P.U. et al.The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis.Nephrol Dial Transplant. 2011; 26: 1327-1339Crossref PubMed Scopus (419) Google Scholar and clinical outcomes after prolonged treatment were reported recently.8.EVOLVE Trial Investigators Chertow G.M. Block G.A. Correa-Rotter R. et al.Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis.N Engl J Med. 2012; 367: 2482-2494Crossref PubMed Scopus (686) Google Scholar Much less is known, however, about changes in bone histology after prolonged therapy with either vitamin D or cinacalcet. Some improvements in bone histology have been described in small studies after treatment with daily oral doses or thrice weekly intravenous doses of calcitriol in adults with sHPT undergoing hemodialysis.9.Brickman A.S. Sherrard D.J. Jowsey J. et al.1,25-dihydroxycholecalciferol. Effect on skeletal lesions and plasma parathyroid hormone levels in uremic osteodystrophy.Arch Intern Med. 1974; 134: 883-888Crossref PubMed Scopus (100) Google Scholar,10.Andress D.L. Norris K.C. Coburn J.W. et al.Intravenous calcitriol in the treatment of refractory osteitis fibrosa of chronic renal failure.N Engl J Med. 1989; 321: 274-279Crossref PubMed Scopus (302) Google Scholar Similar findings were reported after treatment with oral or intraperitoneal doses of calcitriol or with oral doses of doxercalciferol in pediatric patients receiving peritoneal dialysis.11.Salusky I.B. Kuizon B.D. Belin T.R. et al.Intermittent calcitriol therapy in secondary hyperparathyroidism: a comparison between oral and intraperitoneal administration.Kidney Int. 1998; 54: 907-914Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar With regard to cinacalcet, modest improvement in the histological features of sHPT and decreases in bone turnover were noted in one small study after 12 months of treatment,12.Malluche H.H. Monier-Faugere M.-C. Wang G. et al.An assessment of cinacalcet HCl effects on bone histology in dialysis patients with secondary hyperparathyroidism.Clin.Nephrol. 2008; 69: 269-278Crossref PubMed Google Scholar but the effect of cinacalcet on renal bone disease among patients undergoing dialysis has yet to be characterized adequately. Of note, the exploratory end point of fracture rate did not differ in unadjusted analyses in the EVOLVE outcomes study among subjects assigned randomly to treatment with cinacalcet or placebo.8.EVOLVE Trial Investigators Chertow G.M. Block G.A. Correa-Rotter R. et al.Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis.N Engl J Med. 2012; 367: 2482-2494Crossref PubMed Scopus (686) Google Scholar The purpose of the BONAFIDE study described herein was to further assess the skeletal response to cinacalcet treatment among patients with histological evidence of hyperparathyroid bone disease. Bone biopsy and quantitative bone histomorphometry were done before and after treatment. Various biochemical parameters of mineral metabolism were measured at baseline and at regular intervals during follow-up. One hundred and forty-six (146) adult dialysis patients with plasma PTH (PTH) ≥300pg/ml, serum calcium ≥8.4mg/dl, and bone-specific alkaline phosphatase (BALP) >20.9ng/ml underwent bone biopsy during screening (Figures 1 and 2). The biopsy sample was inadequate for histomorphometric evaluation in 11 cases, and 25 subjects were excluded from further study because they did not have biopsy findings consistent with hyperparathyroid bone disease as specified in the study protocol (Figure 2). Notably, 22 of these had normal bone histology and 3 had mixed lesions of renal osteodystrophy, whereas none had adynamic bone.Figure 2Subject disposition by treatment phase.View Large Image Figure ViewerDownload (PPT) Of 110 subjects who entered into the single-arm study and were treated with cinacalcet at a starting dose of 30mg/day, 70 (64%) were men and 91 (83%) were Caucasian. The mean (s.d.) age was 55.2 (14.2) years, range 19–82 years, and the median (interquartile range; IQR) hemodialysis vintage was 43.0 (17.0, 89.0) months. At baseline, 59 subjects (54%) were receiving a vitamin D sterol and 92 (84%) were receiving a phosphate-binding agent and/or calcium supplement. None had been treated previously with cinacalcet. Eighty-four subjects completed the study and 77 underwent a follow-up bone biopsy that provided tissue sufficient for quantitative histomorphometry (Figure 2). All but three subjects were biopsied after approximately 12 months of treatment with cinacalcet. In two subjects, treatment with cinacalcet was stopped after 6 months, and follow-up biopsies were obtained at month 7 in one and at month 8 in the other. A third subject was treated with cinacalcet for 3 months but did not have a follow-up biopsy until month 12. All final results are based upon the 77 subjects with bone biopsy data at baseline and follow-up (Tables 1 and 2). Demographic and biochemical results at baseline for the 33 subjects who did not have paired biopsy specimens before and after treatment also are provided for comparison (Table 3).Table 1Bone histomorphometryaResults are formatted for two dimensions. before and after treatment with cinacalcetBaseline, median (IQR)End of study, median (IQR)P-valuebDescriptive P-values were obtained from the Wilcoxon signed-rank test.B.Ar/T.Ar (%) [14.6–26.9]24.3 (20.2, 30.7)25.3 (20.2, 29.8)0.54O.Ar/B.Ar (%) [0.2–5.8]5.1 (3.5, 7.4)3.8 (2.4, 6.6)0.072O.Pm/B.Pm (%) [10.2–31.7]40.1 (30.3, 50.7)30.7 (21.4, 46.3)0.003O.Wi (μm) [4.1–13.1]9.6 (8.1, 12.3)10.3 (7.9, 14.0)0.17Ob.Pm/O.Pm (%) [1.8–58.3]17.4 (11.8, 26.0)13.9 (6.2, 25.0)<0.001dL.Pm/B.Pm (%) [1.6–15.8]14.5 (9.7, 21.3)8.1 (4.3, 15.0)<0.001E.Pm/B.Pm (%) [0.4–3.4]12.7 (9.9, 16.4)8.3 (6.2, 12.7)<0.001Oc.Pm/E.Pm (%) [0.4–3.4]20.4 (13.2, 27.2)18.0 (13.9, 22.3)0.062Tb.Wi (μm) [90–175]145.5 (124.6, 168.8)153.6 (129.7, 174.6)0.25Tb.N (mm) [1.1–2.2]2.2 (1.8, 2.6)2.1 (1.8, 2.4)0.19BFR/T.Ar (μm2/mm2/day) [97–613]727.8 (545.9, 1052.6)336.1 (172.2, 641.8)<0.0001Mlt (days) [2.4–63]17.8 (10.9, 26.3)21.4 (14.7, 44.0) 25%2 (3%)0Abbreviations: B.Ar, bone area; B.Pm, bone perimeter; dL.Pm, double labeled perimeter; E.Pm, eroded perimeter; Fb.Ar, fibrosis area; Mlt, mineralization lag time; O.Ar, osteoid area; Ob.Pm, osteoblast perimeter; Oc.Pm, osteoclast perimeter; O.Pm, osteoid perimeter; O.Wi, osteoid width; T.Ar, tissue area; Tb.N, trabecular number; Tb.Wi, trabecular width.13.Sanchez C.P. Salusky I.B. Kuizon B.D. et al.Bone disease in children and adolescents undergoing successful renal transplantation.Kidney Int. 1998; 53: 1358-1364Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar,14.Couttenye M.M. D'Haese P.C. Van Hoof V.O. et al.Low serum levels of alkaline phosphatase of bone origin: a good marker of adynamic bone disease in haemodialysis patients.Nephrol Dial Transplant. 1996; 11: 1065-1072Crossref PubMed Scopus (188) Google ScholarContinuous variables are presented as median values with interquartile range (IQR). Numbers in [brackets] denote the lower and upper limit of values for subjects with normal kidney function.13.Sanchez C.P. Salusky I.B. Kuizon B.D. et al.Bone disease in children and adolescents undergoing successful renal transplantation.Kidney Int. 1998; 53: 1358-1364Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 14.Couttenye M.M. D'Haese P.C. Van Hoof V.O. et al.Low serum levels of alkaline phosphatase of bone origin: a good marker of adynamic bone disease in haemodialysis patients.Nephrol Dial Transplant. 1996; 11: 1065-1072Crossref PubMed Scopus (188) Google Scholar, 15.Bervoets A.R. Spasovski G.B. Behets G.J. et al.Useful biochemical markers for diagnosing renal osteodystrophy in predialysis end-stage renal failure patients.Am J Kidney Dis. 2003; 41: 997-1007Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholara Results are formatted for two dimensions.b Descriptive P-values were obtained from the Wilcoxon signed-rank test. Open table in a new tab Table 2Biochemical measurements before and after treatment with cinacalcetBaseline, median (IQR)End of studyaThe end of study value for biochemical parameters is defined as the mean value during the efficacy assessment phase (week 44–52)., median (IQR)P-valuebDescriptive P-values were obtained from the Wilcoxon signed-rank test.PTH (pg/ml) cValues from 74 subjects with measurements both at baseline and at end of study. [10–65]985 (674, 1621)480 (268, 798)<0.001Calcium (mg/dl) [8.4–10.3]9.9 (9.4, 10.3)9.1 (8.6, 9.7)<0.001Phosphorus (mg/dl) [2.2–5.1]5.5 (4.7, 6.2)5.5 (4.9, 6.6)0.94Ca x P (mg2/dl2) [18.5–52.5]53.8 (46.6, 63.9)52.6 (43.2, 62.2)0.050BALP (ng/ml) [2.9–22.4]40.1 (27.3, 73.9)27.7 (18.8, 53.9)0.20N-telopeptide (nmol/l) [5.4–24.2]378 (169, 1304)249 (126, 425)<0.001TRAP (U/l) [0.49–5.31]6.8 (5.1, 9.3)5.1 (3.8, 7.2)0.003Osteocalcin (ng/ml) [11–55.9]494 (245, 846)276 (151, 526.)<0.001Abbreviations: BALP, bone-specific alkaline phosphatase; IQR, interquartile range; PTH, parathyroid hormone; TRAP, tartrate-resistant acid phosphatase.Numbers in [brackets] denote the lower and upper limit of values for subjects with normal kidney function.a The end of study value for biochemical parameters is defined as the mean value during the efficacy assessment phase (week 44–52).b Descriptive P-values were obtained from the Wilcoxon signed-rank test.c Values from 74 subjects with measurements both at baseline and at end of study. Open table in a new tab Table 3Demographic and biochemical characteristics at baseline for subjects with or without bone histomorphometry results after treatment with cinacalcetSubjects included in final analysis (n=77)Subjects excluded from final analysis (n=33)Male sex, n (%)53 (69)17 (52)White race, n (%)63 (82)28 (85)Mean (s.d.) age [range], years54.5 (13.6) [26, 82]56.8 (15.7) [19, 80]Mean (s.d.) height, cm168 (10)167 (10)Mean (s.d.) weight, kg73.7 (17.8)71.6 (18.6)Dialysis duration, median (IQR) Hemodialysis, months43 (17, 89) [n=73]43 (20, 117) Peritoneal dialysis, months37 (16, 53) [n=4]—Use of phosphate binder/calcium supplement, n (%)65 (84)27 (82)Lab values, median (IQR) PTH, pg/ml997 (674, 1621)1322 (752, 2063) Calcium, mg/dl9.9 (9.4, 10.3)10.1 (9.8, 10.5) Phosphorus, mg/dl5.5 (4.7, 6.2)5.7 (5.0, 6.5) Ca x P (mg2/dl2)53.8 (46.6, 63.9)58.6 (50.6, 65.0) BALP, ng/ml40.1 (27.3, 73.9)47.5 (28.8, 74.1) N-telopeptide, nmol/l378 (169, 1304)1041 (277, 1691) TRAP, U/l6.8 (5.1, 9.3)6.9 (4.0, 10.9) Osteocalcin, ng/ml494 (245, 846)671 (373, 1038)Abbreviations: BALP, bone-specific alkaline phosphatase; IQR, interquartile range; PTH, parathyroid hormone; s.d., standard deviation; TRAP, tartrate-resistant acid phosphatase. Open table in a new tab Abbreviations: B.Ar, bone area; B.Pm, bone perimeter; dL.Pm, double labeled perimeter; E.Pm, eroded perimeter; Fb.Ar, fibrosis area; Mlt, mineralization lag time; O.Ar, osteoid area; Ob.Pm, osteoblast perimeter; Oc.Pm, osteoclast perimeter; O.Pm, osteoid perimeter; O.Wi, osteoid width; T.Ar, tissue area; Tb.N, trabecular number; Tb.Wi, trabecular width.13.Sanchez C.P. Salusky I.B. Kuizon B.D. et al.Bone disease in children and adolescents undergoing successful renal transplantation.Kidney Int. 1998; 53: 1358-1364Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar,14.Couttenye M.M. D'Haese P.C. Van Hoof V.O. et al.Low serum levels of alkaline phosphatase of bone origin: a good marker of adynamic bone disease in haemodialysis patients.Nephrol Dial Transplant. 1996; 11: 1065-1072Crossref PubMed Scopus (188) Google Scholar Continuous variables are presented as median values with interquartile range (IQR). Numbers in [brackets] denote the lower and upper limit of values for subjects with normal kidney function.13.Sanchez C.P. Salusky I.B. Kuizon B.D. et al.Bone disease in children and adolescents undergoing successful renal transplantation.Kidney Int. 1998; 53: 1358-1364Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 14.Couttenye M.M. D'Haese P.C. Van Hoof V.O. et al.Low serum levels of alkaline phosphatase of bone origin: a good marker of adynamic bone disease in haemodialysis patients.Nephrol Dial Transplant. 1996; 11: 1065-1072Crossref PubMed Scopus (188) Google Scholar, 15.Bervoets A.R. Spasovski G.B. Behets G.J. et al.Useful biochemical markers for diagnosing renal osteodystrophy in predialysis end-stage renal failure patients.Am J Kidney Dis. 2003; 41: 997-1007Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar Abbreviations: BALP, bone-specific alkaline phosphatase; IQR, interquartile range; PTH, parathyroid hormone; TRAP, tartrate-resistant acid phosphatase. Numbers in [brackets] denote the lower and upper limit of values for subjects with normal kidney function. Abbreviations: BALP, bone-specific alkaline phosphatase; IQR, interquartile range; PTH, parathyroid hormone; s.d., standard deviation; TRAP, tartrate-resistant acid phosphatase. The mean (s.d.) daily doses of cinacalcet among the 77 patients at the end of the titration (week 20), maintenance (week 40), and efficacy assessment phases (week 52) were 67.5 (40.7), 72.3 (46.6), and 73.2 (43.9) mg/day, respectively. Reasons for cinacalcet discontinuation varied as expected (Table 4). Of the 77 subjects, 39 (51%) were receiving vitamin D at baseline and 60 (78%) received vitamin D at some point during the study. The mean (s.d.) weekly dose of vitamin D ranged from 15.9 (10.1) to 21.8 (21.2) μg expressed in μg equivalents of paricalcitol. The types of vitamin D used included oral alfacalcidol only (n=3), oral calcitriol only (n=14), doxercalciferol only (n=4), paricalcitol only (n=21), and other/multiple vitamin D (n=14).Table 4Reasons for cinacalcet discontinuationNo. of subjects (%)Subjects enrolled110Subjects who received cinacalcet110 (100)Subjects who completed the study84 (76)Subjects who completed cinacalcet treatment69 (63)Subjects who discontinued cinacalcet41 (37)Adverse event2 (2)Consent withdrawn4 (4)Administrative decision1 (1)Lost to follow-up2 (2)Death5 (5)Protocol-specified criteria13 (12)Patient request1 (1)Other reason13 (12)Percentages based on number of subjects enrolled. Open table in a new tab Percentages based on number of subjects enrolled. The median (IQR) PTH at baseline was 985 (674, 1621) pg/ml, and values decreased nominally to 480 (268, 798) pg/ml, or by a median (IQR) percent change of -48.3% (-68.8%, -26.5%), after treatment with cinacalcet, P<0.001 (Figure 3). The primary study end point was the change in bone formation rate/tissue area (BFR/T.Ar) from baseline to follow-up during treatment with cinacalcet. The median (IQR) value for BFR/T.Ar at baseline exceeded the upper limit of the normal reference range (97–613μm2/mm2/day),13.Sanchez C.P. Salusky I.B. Kuizon B.D. et al.Bone disease in children and adolescents undergoing successful renal transplantation.Kidney Int. 1998; 53: 1358-1364Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar but it decreased from 727.8 (545.9, 1052.6) to 336.1 (172.2, 641.8) μm2/mm2/day at end of study (EOS), P 800pg/ml (n=52) compared with those with results ≤800pg/ml (n=25); median (IQR) changes were -507 (-748.1, -276.1) μm2/mm2/day and -200 (-369.5, 26.1) μm2/mm2/day, respectively. Subjects who experienced reductions in BFR/T.Ar (n=65) during treatment had higher median (IQR) values at baseline, 816 (595, 1262) μm2/mm2/day, compared with the 12 subjects who did not have a decrease in BFR/T.Ar during follow-up, 425 (154, 592) μm2/mm2/day. The median (IQR) PTH level at baseline also was higher in subjects who had a decrease in BFR/T.Ar during treatment than in those who did not; values were 1113 (693, 1675) and 622 (454, 1110) pg/ml, respectively, at baseline and 536 (313, 959) and 352 (193, 917) pg/ml, respectively, at follow-up in these two groups. Several static histomorphometric measures of bone formation and bone resorption were elevated at baseline but decreased toward normal during treatment (Table 1). The median (IQR) change for osteoblast perimeter (Ob.Pm/O.Pm) was -3.8% (-9.7%, 1.7%), P<0.001, for osteoclast perimeter (Oc.Pm/E.Pm) was -2.1% (-10.6%, 5.8%), P=0.062, and for eroded perimeter (E.Pm/B.Pm) was -3.4% (-6.9%, 0.1%), P<0.001. Bone area/tissue area (B.Ar/T.Ar) did not differ at follow-up compared with baseline. The number of subjects with no peri-trabecular or marrow fibrosis increased from 6 (8%) at baseline to 24 (31%) at EOS (Table 1). Of 71 subjects (92%) with fibrosis at baseline, 21 (27%) had complete resolution at follow-up. The distribution of the various types of renal osteodystrophy changed substantially during the study (Figure 5). At baseline, most subjects had either mild or severe hyperparathyroid bone disease. At EOS, the number of subjects with severe hyperparathyroid bone disease decreased substantially from 13 to 3. Normal bone histology was found in 20 subjects (26%) overall. The number of subjects with mixed uremic osteodystrophy increased from 8 at baseline to 18 at EOS. These subjects generally had a normal BFR/T.Ar with fibrosis but without evidence of impaired mineralization (type 2), which is generally associated with mixed lesions of type 1. Indeed, BFR/T.Ar at EOS was normal (combined with fibrosis) in 13 subjects with mixed lesions, of whom 10 showed an osteoid area <12%. Two subjects with mixed lesions at follow-up had BFR/T.Ar values below the lower limit of normal but also had fibrosis. Two subjects had adynamic bone and one had osteomalacia on follow-up bone biopsy (vide infra). None of the subjects showed positive aluminum staining on bone biopsy. Although biopsies were categorized into the various types of renal osteodystrophy using reference values for BFR/T.Ar obtained originally from children and adolescents, the results did not differ materially when assessed using published values for BFR/T.Ar from adults (Supplementary Figure 1, Supplementary Figure 1 Legend online). Download .jpg (.04 MB) Help with files Supplementary Figure 1 Download .doc (.05 MB) Help with doc files Supplementary Figure 1 Legend As stated previously, PTH levels decreased significantly during treatment with cinacalcet. The changes in PTH (Table 2, Figure 3) correlated positively with changes in BFR/T.Ar (rs: 0.344; P=0.003), E.Pm/B.Pm (rs: 0.310, P=0.007), and trabecular number (rs: 0.318; P=0.006). Serum calcium and Ca x P values were lower compared with baseline during the efficacy assessment phase of the study. The mean (s.e.) changes were -7% (1.1%) and -6.9% (3.1%), respectively. Serum phosphorus levels did not differ. Values for two biochemical markers of resorption, N-telopeptide (NTx) and tartrate-resistant acid phosphatase (TRAP), and for the bone formation marker osteocalcin (OC) were elevated at baseline but decreased at follow-up (Table 2). The median (IQR) percent changes from baseline to week 52 were -39.1% (-62.5%, -13.9%), P<0.001, for OC, -31.6% (-56.0%, 4.1%), P<0.001, for NTx, and -19.9% (-39.7%, 10.0%), P=0.003, for TRAP. No notable change in BALP was observed. In the subset of 20 subjects who had normal bone histology at follow-up, median (IQR) PTH values decreased from 884 (603, 1323) to 283 (164, 453) pg/ml (Table 5). The mean percentage changes in NTx, TRAP, and OC in these subjects were somewhat greater compared with the overall treatment group.Table 5Biochemical measurementsaData are presented as median (interquartile range). in subjects who did or did not have normal bone histology at follow-upNormal histology (n=20)Abnormal histology (n=57)BaselineEnd of studyBaselineEnd of studyPTH (pg/ml) [10–65]884 (603, 1323)283 (164, 453)1124 (681, 1716)606 (319, 1022)BALP (ng/ml) [2.9–22.4]36.6 (27.6, 53.0)18.9 (13.7, 25.0)45.3 (27.3, 90.9)34.2 (20.6, 82.8)N-telopeptide (nmol/l) [5.4–24.2]253 (166, 464)133 (60, 251)540 (169, 1364)303 (167, 762)TRAP (U/l) [0.49–5.31]5.7 (4.1, 8.6)4.1 (3.0, 5.3)7.1 (5.2, 9.4)5.4 (4.1, 7.8)Osteocalcin (ng/ml) [11–55.9]296 (215, 480)156 (107, 234)580 (303, 906)366 (195, 633)Abbreviations: BALP, bone-specific alkaline phosphatase; PTH, parathyroid hormone; TRAP, tartrate-resistant acid phosphatase.Numbers in [brackets] denote the lower and upper limit of values for subjects with normal kidney function.a Data are presented as median (interquartile range). Open table in a new tab Abbreviations: BALP, bone-specific alkaline phosphatase; PTH, parathyroid hormone; TRAP, tartrate-resistant acid phosphatase. Numbers in [brackets] denote the lower and upper limit of values for subjects with normal kidney function. A total of 110 subjects received more than one dose of cinacalcet and were included in the safety population. The mean (s.d.) daily dose of cinacalcet at the end of the titration, maintenance, and efficacy assessment phases was 74.1 (43.6), 75.2 (49.4), and 75.0 (45.5) mg/day, respectively. The most common adverse events (AEs) were nausea (26%), vomiting (21%), diarrhea (20%), arthralgia (14%), hypocalcemia (12%), dyspnea (11%), and muscle spasms (11%). Treatment-related AEs were reported in 47 subjects (43%); these included nausea in 16 (15%), symptomatic hypocalcemia in 12 (11%), vomiting in 10 (9%), dyspepsia in 9 (8%), and diarrhea in 7 (6%). Three subjects had serious treatment-related AEs: symptomatic hypocalcemia, convulsion, and convulsion and symptomatic hypocalcemia, respectively. There were no deaths or life-threatening AEs that were judged to be related to cinacalcet. Only two subjects (2%) had AEs that led to discontinuation of cinacalcet and one subject had an AE that led to withdrawal from the study. Overall, for the safety population, the mean (s.d.) serum calcium was 10.0 (0.7) mg/dl at baseline, 9.1 (0.9) mg/dl at week 20, and 9.2 (0.9) mg/dl at week 52. The mean (s.e.) percent change from baseline in serum calcium ranged from -11.1% (0.9%) to -5.7% (1.1%) over the course of the study. Safety end points for bone mineralization were evaluated by comparing biopsy results at screening and at EOS. Mineralization lag time was highly skewed by extreme values resulting from sample testing, the median (IQR) mineralization lag time at baseline and at EOS was 18 (11, 26) and 21 (15, 44) days, respectively. Double labeled perimeter/bone perimeter (dL.Pm/B.Pm) at baseline was within normal limits in 27 subjects (35%) and elevated in 50 subjects (65%). At EOS, values remained within the normal range in 22 subjects, decreased from elevated values to normal in 28 subjects, and remained elevated in 22 subjects. In the five remaining subjects with initially normal values for dL.Pm/B.Pm, results at follow-up were elevated in four and low in one. Overall, median (IQR) osteoid area/bone area (O.Ar/B.Ar) was unchanged from baseline to EOS with values of 5.1% (3.5%, 7.4%) and 3.8% (2.4%, 6.6%), respectively. This parameter was normal at baseline in 41 subjects (53%) and remained normal in 31 subjects (40%) at EOS. Values were normal initially and became elevated in 10 subjects (13%) and decreased from elevated values to normal in 20 subjects (26%), whereas O.Ar/B.Ar was elevated both at baseline and at EOS in 16 subjects (21%). Two subjects developed adynamic bone as documented by EOS bone biopsy findings of O.Ar/B.Ar <12%, BFR/T.Ar <97μm2/mm2/day, and no evidence of fibrosis. Both subjects had risk factors for adynamic bone that included a normal BFR/T.Ar at baseline with values of 385 and 398 μm2/mm2/day, respectively, and only minimal signs of fibrosis that supported a study diagnosis of hyper
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