Cinacalcet: the chemical parathyroidectomy?

The existing body of evidence suggests that cinacalcet is an effective drug for secondary hyperparathyroidism (SHPT) control in patients undergoing maintenance dialysis (CKD-5D) [1–10]. Indeed, available evidence suggests that by modulating the parathyroid calcium-sensing receptor affinity to serum calcium, cinacalcet lowers by 40–50% (250–350 pg/mL) serum parathyroid hormone (PTH) (Table 1). A consensual reduction in calcium [∼0.5– 0.8 mg/dL (0.125–0.200 mmol/L); 5–8%] (Table 1) is also reported and expected due to the calcium-PTH set point change induced by this drug [11, 12]. However, some, albeit not all, reports (Table 1) have described a consensual reduction in serum phosphorus, which is more complicated to explain and often confounded by the concomitant use of other agents such as vitamin D and phosphate binders that significantly affect phosphorous metabolism [13, 14]. Serum phosphorous represents a minimal part (∼1%) of the total body pool and is regulated by the net amount absorbed in the intestine, the quota excreted by the kidneys and the net amount exchanged by the bones in the time unit [13]. Notably, serum phosphorous does not always closely mirror the total body pool and phosphorous balance in CKD, since different hormones regulate renal tubular (i.e. FGF-23, FGF-7, PTH) and bone (i.e. PTH) phosphate handling to avoid excessive fluctuations of serum phosphorous concentration [13–15]. However, in CKD-5D patients the amount excreted by the kidneys is minimal if not absent. Hence, the reported tendency of cinacalcet to reduce serum phosphorous cannot be explained by a ‘renal compensation’, but rather by the PTH effect on bones. We read with interest the manuscript by Zitt et al. [16]. The aim of their study was to elucidate the mechanisms by which cinacalcet may lower serum phosphorous. In this observational study (ECHO study) [16], the authors report an overall tendency towards phosphate reduction (median change −9.1%, interquartile range: −25% to +10%), after 12 months of cinacalcet therapy [16]. Each 10% serum PTH reduction correlates with a 3% decrease in serum phosphorous in the ECHO study cohort [16]. However, at least 25% of the study population experienced an increase in serum phosphorous (median change −9.1%, interquartile range: −25% to +10%) [16] in spite of the treatment with cinacalcet. The use of other compounds such as vitamin D or phosphate binders as well as the lack of diet control might explain why not all patients treated with cinacalcet exhibit a consensual serum phosphorous reduction, but authors document that among 45% of patients in which serum phosphorous decreases [defined as a change of at least 0.1 mg/dL (0.0323 mmol/L)], the use of concomitant medications cannot explain this trend (vitamin D either increased or remained unchanged and phosphate binders were either reduced or left unchanged during follow-up). Finally, the lack of association between cinacalcet dose and serum phosphorous corroborates the hypothesis that bone metabolism may play a role at least in some patients who experience a phosphate reduction while on cinacalcet treatment, similarly to what was seen after surgical parathyroidectomy [17]. The role of bone metabolism could also be hypothesized by the multivariable-adjusted and sensitivity analyses. Adjustment for factors associated with serum phosphorus in CKD-5D patients documents that baseline serum phosphorous, dialysis vintage and PTH change from baseline to month 12 are the major determinants of phosphorus reduction at follow-up [16]. However, sensitivity analyses document that a significant serum phosphate reduction is noted in all but the lowest baseline PTH quartile and PTH change at Month 12 [17], suggesting that the quota of phosphate removed from the bone is relevant among subjects with severe SHPT or among patients with parathyroid gland tissue still responsive to a calcimimetic drug (i.e. greater PTH reduction). The findings reported by Zitt et al. are consistent with previous reports (Table 1). Though all studies recruited subjects with on average a poorly controlled PTH (in the range of 500–700 pg/mL), not all patients experienced a decrease in serum phosphate. However, no study has controlled the use of phosphate binders and vitamin D changes during follow-up. In this regard, Zitt et al. further expand the body of knowledge showing this trend among patients who did not decrease vitamin D or increase phosphate binder usage at follow-up. Nonetheless, the observational nature and the potential of imbalance among different groups (data not reported) and the lack of phosphate intake evaluation at baseline and during follow-up, caution against definitive conclusions about the role of PTH and the generalizability of the authors’ results.