Parathyroid hormone targets in chronic kidney disease and managing severe hyperparathyroidism

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Mineral bone disorders in chronic kidney disease (CKD) are common and primarily driven by secondary hyperparathyroidism (HPT). Secondary HPT has long been linked with symptoms such as bone pain and itch, as well as increased fracture rates and accelerated vascular and soft tissue calcification, with adverse outcomes including fracture and increased cardiovascular mortality.
The diagnosis and management of these disorders is complex, but measurement and targeting of PTH has been a focus of treatment for decades. Controversy persists as to the optimal PTH target range in CKD, and how this target should change as CKD progresses, as well as how to best manage elevated PTH levels. The aim of therapy is to target a PTH level that results in normal bone turnover with the belief that this might ameliorate the consequent bone problems and metabolic sequelae. However, both measuring and monitoring bone turnover remains challenging.
Current treatment approaches primarily involve attempts to control serum mineral parameters including calcium, phosphate and PTH, and to deliver native and/or pharmacologically active vitamin D or its analogues. The manipulation of serum levels of calcium and phosphate using diet, binders or supplements and dialysis is also usual practice. Calcimimetics (now restricted in Australia), surgical parathyroidectomy and parathyroid tissue ablation with ethanol or calcitriol injection, are usually reserved for severe hyperparathyroidism.
Although often first line therapy, the use of calcitriol or analogues is associated with well‐documented adverse effects including hypercalcaemia and over‐suppression of bone turnover resulting in adynamic bone disease. Thus, the optimal strategy to medically manage HPT, as well as the hierarchy of targets, remains unclear. In particular, the dosing and schedule, and the role of combination therapy (e.g. vitamin D, activated vitamin D and calcimimetic agent) compared with the use of calcitriol alone has yet to be defined.
Approaches to the management of severe HPT vary markedly from clinician to clinician, reflecting the poor evidence‐base for various approaches. There is no internationally accepted definition of severe HPT. In general, this definition might include a combination of high circulating intact PTH (e.g. >9 times upper limit of normal range), accompanied by patient‐level symptoms (pruritus, bone pain and proximal myopathy), evidence of bone disorder (very high bone turnover or cortical bone loss), bone mineral laboratory derangements (hypercalcaemia) and clinical syndromes (calciphylaxis, neuromuscular disturbances and calcific vascular disease).
Another major and persisting problem is the difficulty we have in predicting bone changes from the biochemistry and PTH, because very high serum PTH values are not always indicative of high bone turnover, and low PTH is not necessarily indicative of adynamic bone. Even imaging is currently of little help, and whilst newer methodology is in development,1 in practice, the patterns of bone disease are so complex that the only reliable way of assessing bone histology is currently bone biopsy.
One of the fundamental barriers to evidence‐based approaches to managing HPT relates to the heavy reliance on animal data, in vitro studies, observational associations and small underpowered trials with surrogate endpoints. Nevertheless, some progress has been achieved with the recent randomized controlled trials like PRIMO,2 OPERA3 and EVOLVE.4
This report explores the current and evolving guidelines for management of HPT and provides an Australasian view on current practice issues, implications for patient care and future directions for clinical care and research.

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