Parathyroidectomy in the calcimimetic era

Abstract

SUMMARY:  With the introduction of the calcimimetic cinacalcet HCl, some patients who would previously have undergone parathyroidectomy are likely to remain on medical therapy. Data is available on complication rates and some important outcome measures of parathyroidectomy, but the efficacy of calcimimetics to influence patient-based endpoints such as cardiovascular mortality and renal osteodystrophy has not been established. Nevertheless, cinacalcet HCl has been demonstrated to improve levels of calcium, phosphate, the calcium phosphate product and parathyroid hormone (PTH). Based on available data, parathyroidectomy is proposed as the preferred treatment option when averaged levels of intact PTH (iPTH) exceed 85–95 pmol/L despite optimal therapy. When iPTH levels exceed 50 pmol/L, parathyroidectomy should be considered if levels of serum calcium, phosphate or the calcium phosphate product are above established target ranges or when patients with established osteoporosis have progressive loss of bone mineral density. Because the currently-recommended biochemical targets are difficult to achieve and maintain for many patients on dialysis, parathyroidectomy rates are likely to increase if these management proposals are followed. This highlights the need for prospective studies with ‘hard’ endpoints, to establish evidence-based roles for parathyroidectomy and calcimimetic therapy.

Despite heightened sensitivity to the vascular consequences of elevated levels of parathyroid hormone (PTH), calcium, phosphate and the calcium phosphate product, only 5% of patients on standard therapy achieve K/DOQI targets set for all four indices.¹ The recent introduction of the calcimimetic cinacalcet HCl marks a significant therapeutic advance, because this drug reduces levels of PTH and the calcium phosphate product towards the target range in most patients with mild to moderate secondary hyperparathyroidism (SHPT).² The role of parathyroidectomy needs to be re-evaluated in the calcimimetic era and this review assesses available data on the risks and benefits of surgical and calcimimetic treatments. Guidelines for parathyroidectomy are then proposed, with the intention of promoting debate and of highlighting areas where well-planned research studies are needed if our therapeutic decisions are to be evidence based.

THE ASSOCIATION OF ELEVATED PTH AND DISEASE

Meta-analysis of studies assessing bone histomorphometry suggests a threshold for iPTH of 15.9–21.2 pmol/L (150–200 pg/mL) to achieve 93% sensitivity (95% confidence interval (CI), 87–97%) and 77% specificity (95% CI, 62–87%) for the diagnosis of high bone turnover renal osteodystrophy.³ However, for prevention of vascular disease and cardiac events, which account for around 40% of dialysis patient deaths in Australia and New Zealand, targets are less clear. In a prospective study from Spain, the relative risk (RR) of cardiovascular death (adjusted for age, gender, diabetes, smoking and serum phosphate) was reported to be 3.9 (CI, 1.2–12.9; P = 0.02) for patients with iPTH levels >50 pmol/L, when compared to patients with iPTH levels of 12–50 pmol/L.⁴ A number of important analyses from the USA have now been published, with large patient numbers but a more heterogeneous population base. In one of these, sudden death was more common in patients with iPTH levels >52 pmol/L compared to those with iPTH levels of 9.6–21 pmol/L (RR 1.25: P < 0.05), after adjustment for levels of phosphate and the calcium phosphate product.⁵ Another study reported survival data on 46 437 patients treated with haemodialysis through the Fresenius Medical Care dialysis chain.⁶ Baseline data were collected and averaged over 6 months and patients were designated to have ‘attained’ or ‘not attained’ target values for PTH and the calcium phosphate product. Over the subsequent 6 and 12 months of follow up there was a significant difference in mortality if both the PTH and the calcium phosphate product targets were attained versus neither attained (P < 0.001). However, when assessed independently, PTH levels did not significantly influence survival. In a more recent analysis utilizing the Fresenius database, PTH levels >64 pmol/L were reported to be associated with an increased relative risk of death in multivariate, but not univariate, analysis.⁷ The majority of this risk was attributed to patients with PTH levels over 95 pmol/L.

It is not unexpected that large patient numbers are required to detect an association between PTH and mortality, because multiple pathways are likely to mediate the development of vascular calcification. Calcium and phosphate levels are likely to influence vascular calcification by effects on the vascular sodium-phosphate cotransporter, Cbfa-1 gene expression and the transdifferentiation of vascular smooth muscle cells to cells with phenotypic features of osteoblasts.^8–10 Other potential mediators, not directly influenced by PTH, include reduced levels of BMP-7, reduced calcium binding by fetuin A and altered vascular smooth muscle cell regulation by PTHrP.^11–13

RISKS AND BENEFITS OF PARATHYROIDECTOMY

Using data from the United States Renal Database System (USRDS), the rate of parathyroidectomy has been calculated as 7.16 per 1000 person-years at risk.¹⁴ After a slight rise during the early 1990s, adjusted parathyroidectomy rates between 1995 and 1999 declined by approximately 30%, possibly reflecting improved medical therapy. Rates were higher among patients who were younger, female, non-diabetic, receiving peritoneal dialysis and those with a longer cumulative duration of dialysis. Data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) shows that the rate of parathyroidectomy in the USA is lower than other developed countries, with a relative risk for parathyroidectomy in the UK 3.18-fold that of the USA, and in Spain 4.06-fold that of the USA.¹

There is no doubt that subtotal parathyroidectomy or total parathyroidectomy with autotransplantation (AT) is effective therapy, despite a relatively high incidence of recurrent hyperparathyroidism or persisting hypoparathyroidism in some studies.^15–17 In one informative study, 148 patients undergoing parathyroidectomy were matched with dialysis patients not undergoing the procedure and followed for 5.2 ± 3.9 years.¹⁸ In 129 of these patients, a total parathyroidectomy with AT was performed, and in 19 patients with only three glands identified and removed, AT was not performed. Levels of iPTH, calcium, phosphate, the calcium phosphate product and alkaline phosphatase (ALP) all fell significantly at 1 year (mean iPTH 149 to 16 pmol/L, calcium 2.65 to 2.38 mmol/L, phosphate 2.21 to 1.66 mmol/L, calcium phosphate product from 4.96 to 3.75 mmol²/mmol² and ALP from 737 to 253 IU). Importantly, these improvements were maintained at both 2 and 5 years. Recurrence of SHPT occurred in 22%, requiring medical therapy (16 patients), repeat neck exploration (4) or removal of AT (13), and there was a low complication rate with only one postoperative death related to cardiac failure.

Data from the USRDS has also been used to assess mortality rates for 4558 dialysis patients undergoing parathyroidectomy, compared with 4558 non-randomised but matched controls.¹⁹ Patients were followed from the date of parathyroidectomy until death or loss to follow up. The 30-day postoperative mortality was high at 3.1%, with 50% of deaths due to cardiovascular and 18% to infective causes. In comparison, the 30-day mortality was 1.2% for matched controls (95% CI, 0.9–1.6). Nevertheless, the long-term RR of death among patients undergoing parathyroidectomy was 10–15% lower than that of matched controls. Survival curves for the two groups crossed 587 days after parathyroidectomy, with a median survival of 53.4 months (95% CI, 51.2–56.4) after parathyroidectomy versus 46.8 months (95% CI, 44.7–48.9) for controls.

Patients often require high doses of calcium and calcitriol after parathyroidectomy. Whether this therapy worsens vascular calcification in some patients is unknown, but vascular calcification has been reported to remain stable or regress in patients who maintain a calcium phosphate product <4.2 mmol²/L².²⁰ Improved levels of haemoglobin, reduced use of epoietin and improved quality of life have also been reported after parathyroidectomy for SHPT.^21–23

In summary, patients treated surgically for SHPT achieve biochemical targets up to 5 years from surgery. Rates of recurrent hyperparathyroidism are comparable for total and subtotal parathyroidectomy, but hypoparathyroidism occurs more often with total parathyroidectomy, so a subtotal procedure or parathyroidectomy with AT is generally preferred.^16,20 Patients treated surgically for SHPT have improved long-term mortality compared to patients on standard medical therapy.

NON-SURGICAL ABLATIVE TECHNIQUES

Selective percutaneous ethanol injection therapy and direct calcitriol or vitamin D analogue injection therapy have been suggested as alternatives to parathyroidectomy.^24,25 Guidelines for the use of these techniques are based on the concept that diffusely hyperplasic glands will respond to medical therapy but that enlarged glands, containing areas of nodular hyperplasia, will be unresponsive and should be ablated.²⁶ In some studies, calcitriol or a vitamin D analogue has been used in place of ethanol to reduce side-effects and surrounding tissue damage. However, percutaneous injection therapy was reported to be ineffective in a recent study and maxacalcitol (a vitamin D analogue) has been reported to cause tissue damage similar to that produced by ethanol.^27,28 Therefore, the role of percutaneous injection therapy in management of SHPT remains uncertain.

GAUGING A ‘POINT OF NO RETURN’ FOR MEDICAL THERAPY

Secondary hyperparathyroidism progresses from diffuse hyperplasia to monoclonal nodular hyperplasia. Glands with nodular areas are more likely to be refractory to medical therapy, due to lower levels of calcium-sensing receptors (CaR), vitamin D receptors and the cyclin-dependent kinase inhibitors p21 and p27, which regulate the G(1) to S phase of cell cycling.^29,30 Nodular hyperplasia has been reported to be present in over 85% of glands weighing more than 500 mg and patients with at least one parathyroid gland with a diameter exceeding 1 cm have been reported to be refractory to calcitriol pulse therapy.^31,32

Ultrasound has been proposed as a means of detecting enlarged glands not likely to respond to medical therapy. Unfortunately, the technique is frequently inaccurate and nodular hyperplasia has been reported in up to 88% of glands below 0.5 cm³.²⁷ Therefore, at present, imaging techniques do not reliably distinguish responsive from unresponsive patients.

RISKS AND BENEFITS OF CALCIMIMETICS

The newly registered calcimimetic cinacalcet HCl (Sensipar, Amgen Thousand Oaks, CA, USA) is a synthetic small organic compound that binds to the transmembrane region of the CaR and increases its sensitivity to extracellular ionized calcium levels. This shifts the calcium set-point of PTH to the left and reduces PTH release across a wide range of ionized calcium concentrations. A number of randomised placebo-controlled trials have confirmed that cinacalcet HCl effectively reduces levels of PTH, calcium, phosphate and the calcium phosphate product.^2,33–37 Patients treated with cinacalcet HCl plus standard therapy achieved K/DOQI targets for PTH and the calcium phosphate product significantly more often than patients on standard therapy (56 vs 10% and 65 vs 36%, respectively; P < 0.001).² However, only 18% of patients with baseline iPTH levels over 85 pmol/L achieved both the iPTH and calcium phosphate product targets after 18 weeks treatment. Some evidence for fracture reduction has been derived from post-hoc analysis of these trials but, despite improved bone turnover markers, no effect has been reported for bone histomorphometry.^38,39 To date, cinacalcet HCl has not been shown in randomised controlled trials to significantly influence quality of life, levels of haemoglobin, the use of epoietin, reduction in use of standard phosphate binders, calcitriol or vitamin D analogues, rates of hospitalization or all-cause mortality. However, interim data suggests that when SHPT is not severe, K/DOQI biochemical targets may be met using cinacalcet plus lower ‘physiological’ doses of intravenous vitamin D.^40,41 Gastrointestinal side-effects occur more commonly in patients on cinacalcet than placebo and, because the drug inhibits cytochrome P-450 2D6, patients taking flecainide, thioridazine and most tricyclic antidepressants have been excluded from studies.

In summary, calcimimetics improve the achievement of biochemical targets, likely to influence long-term bone and cardiovascular outcomes. Data is currently lacking to support a direct impact on cardiovascular survival, bone histomorphometry or quality of life.

PROPOSED GUIDELINES FOR PARATHYROIDECTOMY

In view of these data, and using proposed Caring for Australians with Renal Impairment (CARI) biochemical targets,⁴²Table 1 provides a graded approach to SHPT management and guidelines for parathyroidectomy. If followed, these management guidelines would lead to increased rates of parathyroidectomy and probably to better outcomes for patients with severe hyperparathyroidism. Parathyroidectomy rates might also increase for patients with moderate SHPT, particularly if cost considerations exclude the widespread use of cinacalcet HCl and newer phosphate binders.

Table 1.  Recommendations for management of secondary hyperparathyroidism

1. Use standard therapy (generally calcium-based phosphate binders and calcitriol) to achieve proposed CARI targets, which are slightly lower than earlier K/DOQI targets.

• Intact-PTH: 1–3 times the upper range of the assay.

• Corrected serum calcium: ≤2.4 mmol/L.

• Serum phosphate: ≤1.6 mmol/L.

• Ca × PO4 product: ≤4 mmol^2/L^2.

Use values averaged over 3–6 months.

2. For patients not achieving target values:

• Increase dialysis dose if possible.

• For hyperphosphataemia, use sevelamer or lanthanum carbonate (if available) when treatment with calcium or low dose aluminium-based binders is unacceptable.

3. For above target iPTH ± Ca × PO4 product despite optimal standard therapy:

• Trial of cinacalcet HCl (if available).

4. Indications for parathyroidectomy:

a. Averaged iPTH > 85–95 pmol/L despite optimal available therapy.

b. Averaged iPTH > 50 pmol/L despite optimal available therapy in addition to

i. Levels of corrected serum calcium >2.4 mmol/L or

ii. Levels of serum phosphate >1.60 mmol/L or

iii. Ca × PO4 product >4 mmol^2/L^2 or

iv. Progressive loss of hip or lumbar spine bone mineral density in patients with osteoporosis on optimal therapy.

In this era of ‘medical parathyroidectomy’, a therapeutic trial of cinacalcet HCl would seem reasonable in many patients with SHPT prior to consideration of surgery. A strong case also exists for its availability to treat patients unsuitable for surgery or waiting for elective surgery. However, prospective studies are needed to assess outcomes of cinacalcet plus standard therapy versus parathyroidectomy and, most importantly, to assess the influence of cinacalcet on patient-based outcomes. Without such studies, important management decisions will remain based on opinion rather than evidence.