A single-centre retrospective analysis of cinacalcet therapy in primary hyperparathyroidism

Patient selection

All patients seen in the pHPT clinic between March 2019 and July 2020 were assessed for eligibility. Every patient who received a prescription of cinacalcet under the pHPT clinic was taken forward for review, including those who started cinacalcet prior to March 2019 and those who subsequently ceased therapy for any reason.

Eligibility criteria for starting cinacalcet at the pHPT clinic are described in the local shared care pathway summarised in the Supplementary Appendix. Additionally, during the first wave of the COVID-19 pandemic, a small number of patients were treated with cinacalcet who were symptomatic at a lower serum calcium threshold, to avoid hospitalisation.

This study was approved as a service evaluation in Cambridge University Hospitals NHS Foundation Trust (local project ID 9049).

Data collection

Electronic patient records (EPRs) were accessed in the local e-hospital system to assess the start date of cinacalcet therapy, biochemistry results, date of dose adjustment, adverse effects and date of cessation. Symptoms at presentation and during treatment were not recorded on a specific pro forma in the EPR. Prescriptions for cinacalcet were not directly recorded in the EPR so the date of initiation, adjustment and cessation were taken from EPR notes describing these events.

Biochemistry was assayed in the Trust laboratory and accessed from the EPR: serum calcium (Ca, mmol/L), adjusted serum calcium (aCa, mmol/L), serum phosphate (PO, mmol/L), parathyroid hormone (PTH, pmol/L) and estimated glomerular filtration rate (eGFR, mL/min/1.73 m², capped at 90 mL/min/1.73 m² by the Trust laboratory). External results supplement those from the Trust laboratory in a small number of patients where biochemistry was assayed by external laboratories. The baseline bloods were determined as the last results reported before cinacalcet initiation, and the post-treatment bloods were determined as either the most recent bloods where treatment continues or the final bloods before treatment cessation where therapy ceased for any reason.

Patients were further subdivided for analysis into those receiving lower dose cinacalcet therapy (cinacalcet dose ≤ 30 mg/day (15 mg/day or 30 mg/day)) and those receiving higher dose cinacalcet therapy (cinacalcet dose > 30 mg/day (45, 60 or 90 mg/day]). The data that support the findings of this study are available on request from the corresponding author.

Statistical analysis

Statistical analysis was performed using free online software (www.socscistatistics.com); a non-paired t-test was used in the analysis of post-treatment biochemistry in low vs high dose cinacalcet therapy, and a paired t-test was used for the analysis of pre- vs post-treatment biochemistry. A P -value of <0.05 was considered statistically significant. Mean values are presented ± s.d. Median values are presented with the range in parentheses.

Literature search

The Medline database was searched in May 2020 using the following strategy: (cinacalcet or mimpara or sensipar) AND (primary hyperparathyroidism).

Cohort characteristics

Three hundrerd and six patients were seen in the pHPT clinic during this period; 86 were started on cinacalcet and taken forward for review. The 220 patients who did not commence cinacalcet either did not meet the inclusion criteria as set out in our shared care policy (see Supplementary Appendix) or elected not to receive medical treatment with cinacalcet; eligible patients were offered PTX. The majority of our cohort was female (72 patients) with a median age of 77 years (31–94 years). Most patients were symptomatic with hypercalcaemia at presentation (64 patients), most commonly muscle pain or weakness (18 patients), bone pain (17 patients), fatigue or lethargy (15 patients), constipation (12 patients), confusion (12 patients) and polyuria (10 patients).

Baseline mean Ca (2.92 mmol/L ± 0.12 mmol/L), aCa (3.01 mmol/L ± 0.11 mmol/L) and PTH (19.5 pmol/L ± 10.12 pmol/L) exceeded the reference range; mean PO (0.88 mmol/L ± 0.18 mmol/L) was in the lower end of the normal range and mean eGFR was normal (71.1 mL/min/1.73 m² ± 18.6 mL/min/1.73 m²) (Table 1). Forty-two patients had a baseline Ca or aCa > 3.00 mmol/L. Thirty-seven patients had a baseline Ca or aCa between 2.90 and 3.00 mmol/L. During the first wave of the pandemic, seven patients were treated with a baseline Ca and aCa above the normal range but <2.90 mmol/L in an effort to reduce or avoid hospital attendance. Six out of these seven patients had documented symptoms of hypercalcaemia (confusion in two patients, polyuria/polydipsia in two patients, unspecified in two patients), and the seventh patient had been receiving cinacalcet under a private endocrinologist pre-dating enrolment with the pHPT clinic. However mean baseline chemistry was near identical prior to first wave of the pandemic and within the opening 4 months of the pandemic. The majority of patients commenced cinacalcet 30 mg/day (78 patients) with the remainder at 60 mg/day (eight patients).

Those patients requiring higher doses of cinacalcet (>30 mg/day) had significantly higher baseline PTH than those using lower doses (≤30 mg/day; P < 0.05). Baseline Ca and aCa were higher, and PO was lower in patients requiring higher doses of cinacalcet (>30 mg/day) but did not reach statistical significance (P > 0.05 in all parameters; Table 1).

Outcomes from cinacalcet therapy

Cinacalcet dosage was adjusted by endocrinologists to achieve a target Ca < 2.70 mmol/L. Overall, 68 patients achieved a target Ca with cinacalcet at a mean daily dose of 39.4 mg ± 17.1 mg/day; no patient received a dose > 90 mg/day (range, 15–90 mg/day). The majority of patients (47 patients) commenced on lower dose cinacalcet (30 mg/day) achieved a target Ca without requiring a full licensed dose of 60 mg/day. The median duration of treatment was 35 weeks (1–178 weeks). In those patients achieving a target Ca, the median time to achieve a target Ca was 5 weeks (1–80 weeks); patients taking lower doses of cinacalcet ≤30 mg/day achieved a target Ca sooner than those taking higher doses of cinacalcet > 30 mg/day, but this was not significant (median 5 weeks (range 1–80 weeks) vs 7 weeks (range 1–47 weeks), P = 0.158).

Throughout the treatment period across the entire cohort, mean Ca fell significantly into the normal range (2.52 mmol/L ± 0.22 mmol/L, P < 0.001), mean aCa and PTH fell significantly but remained above the normal range (2.63 mmol/L ± 0.21 mmol/L P < 0.001 and 18.9 pmol/L ± 13.9 pmol/L, P < 0.001, respectively), mean PO rose significantly though remained in the normal range (1.01 mmol/L ± 0.12 mmol/L, P < 0.005) and mean eGFR fell but non-significantly (69.7 mL/min/1.73 m² ± 19.8 mL/min/1.73 m², P = 0.1123) (Fig. 1). Changes in symptoms associated with hypercalcaemia were not recorded in the EPR such that data could be collected to assess change in symptoms while on cinacalcet.

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Biochemical responses across the entire cohort, pre- and post-treatment with cinacalcet.

Citation: Endocrine Connections 10, 11; 10.1530/EC-21-0258

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Additionally, a ROC curve analysis was performed to determine the optimal baseline PTH threshold for initiating cinacalcet at the higher dose of 60 mg/day; positive patients in this analysis were those patients requiring dose adjustment to above initial lower dose of 30 mg/day. A baseline PTH threshold of 25 pmol/L yields 87% specificity and 50% sensitivity, and a threshold of 30 pmol/L yields 98% specificity and 32% sensitivity for indicating those patients likely to require a dose of cinacalcet 60 mg/day (Fig. 2).

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ROC curve; patients requiring cinacalcet > 30 mg/day were considered positives. AUC = 0.777. ^aPTH 25 mmol/L and ^bPTH 30 mmol/L.

Citation: Endocrine Connections 10, 11; 10.1530/EC-21-0258

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Twenty-six patients failed to achieve target Ca on their initial cinacalcet dose, and poor adherence was identified in ten of these patients, most commonly intentional dose reductions/omissions due to nausea (four patients) or headaches (one case), along with problems obtaining a supply of medication (three patients) and unintentional non-adherence due to confusion (two patients).

Cinacalcet used pre-PTX

Twenty-four patients received cinacalcet prior to PTX (Table 2). Seventeen patients were symptomatic (most commonly fatigue/lethargy in 11 patients, bone pain in 9 patients, polyuria in 4 patients), including 6 patients with Ca and aCa < 3.00 mmol/L. Twenty-one patients were treated for parathyroid adenoma, with one case of parathyroid hyperplasia (single gland removed), one case of ectopic parathyroid adenoma (two previous surgical interventions) and one case of equivocal parathyroid adenoma/hyperplasia. All patients started cinacalcet at a low dose of 30 mg/day, though final doses of cinacalcet prior to surgery were higher in this subgroup than the overall cohort mean (44.3 mg/day ± 21.4 mg/day vs 39.4 mg/day ±17.1 mg/day). Fifteen patients achieved target calcium (mean 2.66 mmol/L ± 0.20 mmol/L, median time to target 6 weeks (4–35 weeks)).

Eighteen of these patients had post-operative biochemistry recorded locally within 3 weeks following surgery, mean post-operative Ca 2.40 mmol/L ± 0.14 mmol/L, aCa 2.42 mmol/L ± 0.20 mmol/L and PO 1.22 mmol/L ± 0.25 mmol/L. There were two cases of post-operative hypocalcaemia amongst this subgroup; one patient taking cinacalcet 90 mg/day (highest dose in our cohort) required i.v. calcium and remained an inpatient for 96 h. It should be noted that this patient had a history of two previous parathyroid surgeries and the removal of a single histologically proven normal parathyroid gland during a previous surgery. The third and final surgery for this patient included a hemi-thyroidectomy to remove an intrathyroidal parathyroid adenoma. The second patient that developed post-operative hypocalcaemia was discharged following a targeted surgery for single gland disease on the same day with oral calcium and alfacalcidol.

Adverse effects attributed to cinacalcet

Sixteen patients reported adverse effects though most were tolerated; only four patients found cinacalcet intolerable and ceased treatment. Nausea and vomiting were the most commonly reported adverse effects in seven patients and caused treatment cessation in three patients. One further patient ceased treatment due to headaches. Hypocalcaemia occurred in four patients though was noted more frequently in patients commenced on 60 mg/day (2 patients out of 8 started on 60 mg/day) vs 30 mg/day (2 patients out of 78 started on 30 mg/day). In all patients, hypocalcaemia resolved with dose reduction permitting the continuation of cinacalcet and all subsequently achieved target Ca. Overall frequency of intolerable adverse effects was similar across low dose cinacalcet ≤ 30 mg/day (3 recorded in 62 patients) and high dose cinacalcet > 30 mg/day (1 in 24).

One patient elected to withdraw all active treatment modalities including cinacalcet for pHPT but reported no adverse effects prior to discontinuation.

Literature search

Using our search strategy, 278 results were returned, yielding 10 trials and case series reviews which were appraised (Table 3).

Our cohort is the second largest single-centre cohort and among the oldest reported with a median age of 77 years old (nine out of ten cohorts in the literature reporting a mean age under 70). Baseline biochemistry was similar to our cohorts. A variety of assay methods and reference ranges were utilised in the various studies, accordingly, biochemical targets varied between studies. Our target for titration was among the most lenient at Ca < 2.70 mmol/L; most papers targeted Ca < 2.58 mmol/L. Half of the papers reported a mean dose of cinacalcet below the licensed dose of 60 mg/day, though ours were the lowest reported mean dose. In all papers, mean Ca/aCa normalised and mean PO rose within the normal range. Mean PTH fell in all papers, though normalisation was only seen in a single study (13).

Seven out of the eight papers reporting on the proportion of patients achieving biochemical remission, recording similar outcomes to our study with 68–83% of patients reaching a target Ca or aCa. The remaining paper studying patients with MEN1 was able to achieve target biochemistry in 100% of patients, though this was the smallest reported cohort (13). Two studies (9, 18) noted that higher baseline biochemical parameters, including PTH, correlated with a higher final dose of cinacalcet, in line with our study findings. Thresholds for initiation at a higher dose of cinacalcet were not discussed in the literature.

Limitations

There were limitations to our analysis largely related to the retrospective design. A standardised pro forma was not used in the assessment of pre- or intra-treatment symptom improvement on cinacalcet in the pHPT clinic, and changes in symptoms on treatment were not consistently recorded, as such we cannot draw conclusions as to whether cinacalcet improves symptoms of hypercalcaemia, either for long-term medical treatment or for bridging prior to PTX. We were unable to analyse other sequelae of pHPT including changes in bone mineral density and nephrolithiasis as these were not consistently recorded across the cohort; although it should be noted that current evidence does not consistently demonstrate improvement in these aspects with cinacalcet. Vitamin D was neither consistently tested prior to treatment nor was it recorded whether patients were taking supplementary vitamin D prior to or during treatment with cinacalcet. This was a non-controlled analysis, which further limits the scope of conclusions that can be drawn from these data.