The calcimimetics cinacalcet has been shown to lower plasma PTH effectively among patients with secondary hyperparathyroidism due to chronic kidney disease, but the impact of treatment of histology and bone turnover had not been previously assessed. The study was therefore to study the effective treatment of cinacalcet on bone histology among adults, with biochemical evidence of secondary hyperparathyroidism receiving conventional hemodialysis.
Patients who were receiving standard thrice weekly hemodialysis for greater than or equal to one month that were medically stable and had had biochemical evidence of secondary hyperparathyroidism were eligible. The patients were permitted to receive phosphate binding agents and/or Vitamin D sterols. Additional eligibility criteria included age equal to or greater than 18. Albumin adjusted serum calcium concentration of greater than or equal to 2.1 mmol/L, hemoglobin level to 90 g/L or hematocrit greater than 27 per cent.
In patients receiving Vitamin D sterols, the dose had to stay the same for at least 30 days prior to the start of the study. Exclusion criteria were the use of this bisphosphonates or fluoride in 3 months previous to the study onset.
This was a randomized, placebo-controlled, double blind study conducted between October 2001 and May 2003.
17 centers in the US and Europe took part. The study was 3 phases: 30-day screening, 24-week dose-titration, and 28 week maintenance phases. Eligible patients were assigned randomly in a 2:1 ratio to receive either active cinacalcet or placebo by a computer generated randomization sequence.
In the active treatment arm, dose-titrations started 30mg of cinacalcet or placebo daily and increased incrementally to 50, 70, 90, 120 and 180 mg/day to achieve target plasma PTH level of less than 20 pmol/l. The dose of the study medication could be up-titrated every 4 weeks unless the PTH from the preceding visit was less than 20 pmol/l and/or the maximum dose of 180 mg had been reached or the serum calcium was less than 7.8mg/dl or the patient experiences symptoms of hypocalcemia or an adverse event that prevented increase in dosing.
During the maintenance phase of 28 weeks, the dose of the study medication could be increased if the plasma PTH was greater than 20 pmol/l or the dose could be reduced if the PTH was less than 10 pmol/l on two consecutive study visits, the serum calcium was less than 1.88 mmol/l or the patient had symptoms of hypocalcemia.
There were no restrictions to the dose or type of phosphate binder used. Treatment with vitamin D sterols was permitted with guidelines to maintain constant doses in individual patients. However, changes in the dose were permitted for safety (i.e, dose could be reduced if calcium was high, serum phosphate was high or if calcium phosphate product was high or if PTH was less than 10 on two consecutive visits). Increased doses of vitamin D sterols were permitted if plasma PTH increased by more than 50% from baseline or if serum calcium was less than 2.1 mmol/L.
Bone Histomorphometry was done on biopsy specimens obtained from the anterior iliac crest.
• Two bone specimens were collected from each patient. One at screening and one after 52 weeks of follow-up, or at early termination. Double tetracycline labeling was done for each bone biopsy. Two investigators from the same laboratory evaluated and interpreted the bone biopsies independently using parameters measured in the terminology used to report the results as per guidelines established by the American Society for Bone and Mineral Research.
Biochemical assessments included plasma PTH levels as well as serum levels of calcium, phosphorus, bone-specific alkaline phosphatase and N-telopeptide. A central lab facility was used and serum calcium levels were corrected for albumin.
Primary objective was to compare the interval changes in bone histomorphometry using activation frequency, bone formation rate/bone surface, number of osteoblasts and osteoclasts/bone perimeter, fibrosis surface/bone surface and woven osteoid surface/bone surface in each treatment group.
Secondary endpoints included absolute and percentage changes from baseline in iPTH, bone-specific alkaline phosphatase, serum N-telopeptide and calcium phosphate product.
48 patients were assigned to treatment with either cinacalcet (n=32) or placebo (n=16). 28 of the active treatment patients and all of the placebo treatment completed the 24 week titration phase where as only 20 of the active treatment and 13 of the placebo completed the full 52 week study. Patients with baseline and post treatment bone histomorphometry data included 19 active treatment patients and 13 placebo treatment patients.
Bone histomorphometry Results
There was considerable heterogeneity at baseline for all of the histomorphometric parameters within each treatment group. At the end of the study, median values for static parameters of bone reabsorption and formation and for dynamic parameters of formation and turnover were lower than baseline values in patients given cinacalcet. Bone turnover also decreased in placebo treated patients. Adynamic bone disease did occur in three patients receiving cinacalcet.
Biochemical Endpoint Results
Plasma PTH progressively decreased with the use of active cinacalcet and increased in placebo patients. By 52 weeks, plasma PTH levels were significantly lower in the active treated patients. The average dose for this was 109mg/day for patients who achieved a PTH level of less than 25pmol/L. The serum levels of bone serum alkaline phosphatase and N-telopeptide also decreased from baseline with active treatment. Serum calcium levels decreased modestly among active treated patients and serum phosphate did not differ significantly, although there was a trend towards decrease with active cinacalcet treatment.
The study was randomized control trial and patients were assigned a 2:1 active treatment versus placebo control. The intervention was the use of cinacalcet versus a placebo control. However, as in other areas of mineral metabolism, the use of vitamin D and phosphate binders as well as active vitamin D sterol was used. Half of the patients in each of the active treatment and placebo groups were receiving a vitamin D sterol upon entering the study. Some patients had vitamin D therapy withheld because of increased calcium and or phosphate.
During the study, about 65% of the active treated patients and 55% of the placebo were given vitamin D sterol. The weekly doses were Paricalcitol 20mg, and intravenous calcitriol 3µg, and oral calcitriol 3µg. The portion of the patients taking phosphate binding agents remains constant during this study with 95% of the cinacalcet treated and 85% of the placebo treated patients. The use of non-calcium based phosphate binders was lower in the cinacalcet treated group; however, there were more patients on a combination of calcium and non-calcium based binders. The mean plasma PTH level at the start of the trail was around 70pmol/L in both groups and was decreased by about 50% in the cinacalcet treated group.
Impact on Practice
This study shows that the use of cinacalcet can decrease bone formation and turnover in over one year of treatment. The percentage changes in PTH level, bone serum alkaline phosphatase, serum N-telopeptide and changes in activation frequency, bone formation rate and number of osteoblasts correlated significantly with the cinacalcet group. However, this study also shows that over suppression of the PTH level can result in Adynamic or low turnover bone disease.
This study also shows some of the difficulty in correlating PTH levels with bone histomorphemetric parameters. Overall, the use of cinacalcet does need to me monitored, such that the PTH levels are not over suppressed as this seems to reflect the development of low turnover (Adynamic) bone disease. It is still unclear as to when the optimal time to start the calcium sensing receptor cinacalcet is during the course of chronic kidney disease and changes in bone mineral metabolism.
Unfortunately, due to restrictions on funding, limiting the use of cinacalcet and the lack of evidence related to decrease morbidity or mortality, the use of cinacalcet as mainstay therapy remains uncertain. The use of vitamin D sterols appears to be higher than what would be seen in Canadian centers, and the data linking the start of the vitamin D sterol or increased dose in the setting of low calcium not associated with symptoms remains questionable as well.
Reviewed by Reviewed by Dr. Steven Soroka
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