‘Understanding and Managing Primary Hyperparathyroidism – Anything New?’


powered and controlled data exploring cardiovascular involvement in mild, asymptomatic PHPT are minimal. Despite this, there is some evidence for subtle cardiovascular changes, including left ventricular hypertrophy, carotid-artery intimal thickening and vascular stiffening.4,13–16


Natural Progression of Asymptomatic Primary Hyperparathyroidism


Rubin et al. followed 116 asymptomatic PHPT patients for 15 years with and without parathyroidectomy (PTx).17


Biochemical and


densitometric data from non-surgical patients indicate stability for around a decade; however, this is not indefinite.17


Deterioration


was observed within 15 years, with bone loss particularly apparent at the femoral neck and distal one-third radius, highlighting the importance of regular monitoring (see guidelines in Table 2).17,18 The observational nature of the study and low number of patients completing the 15-year period means that the results require cautious interpretation.4,17


Currently, there are insufficient data to


comment on the natural progression and management of the recently described normocalcaemic PHPT (i.e. PHPT presenting with normal serum calcium levels).4,18,19


Treatment during the Asymptomatic Phase Asymptomatic PHPT brings with it new challenges, particularly in terms of treatment strategies. The aim of PHPT treatment remains to normalise serum calcium and PTH levels and improve any symptoms of disease. In symptomatic patients, PTx is the only definitive treatment for PHPT.18 PTx in all patients,20


While it is reasonable to consider advocating surgery in patients who are outwardly healthy and symptom-free is less straightforward.21


Bone mineral density (BMD) increases at the distal radius, lumbar spine and hip have been shown to persist 15 years later.17 Several studies also support psychological improvements (measured using either the Symptom Checklist 90 or the Comprehensive Pathological Rating Scale) and increased QoL (measured with a 36-question health survey) following PTx.18,21,23–25


PTx can successfully normalise biochemical markers in up to 95% of patients.22


Despite this, no


correlation between test parameters and serum calcium/PTH levels was reported (see Table 3).18,21,23–25


While growing evidence supports the reversal of skeletal and psychological PHPT symptoms after PTx, the results of other studies are contradictory.26


These inconsistencies and the limited


data available mean that alteration of treatment guidelines is not yet warranted.27


Targeted Medical Management


Where PTx is not a clear option, non-surgical follow-up can be sustained for up to eight years with appropriate biochemical and densitometric monitoring (for a recommended follow-up schedule and PTx criteria see Table 2).4,18


In other patients, surgery


may be contraindicated or the patient may not consent. Such patients must likewise be frequently monitored and dietary intake of vitamin D and calcium managed.18


In a short pilot study,


vitamin D supplementation was shown to reduce PTH levels and decrease bone turnover without exacerbating hypercalcaemia.28 More specifically targeted medical management addresses the pathophysiological features of PHPT, including antiresorptives or calcimimetics.18


EUROPEAN ENDOCRINOLOGY


Antiresorptives provide skeletal protection, counteracting damage due to bone loss caused by PHPT. For example, hormone-replacement therapy is effective at increasing BMD in post-menopausal women with PHPT and limits the damaging effects of osteopenia.29 Alendronate is another widely-used, potent, antiresorptive bisphosphonate. It inhibits osteoclast-mediated bone resorption and suppresses bone turnover.30


In a two-year placebo-controlled trial,


patients with asymptomatic PHPT (n=44) receiving alendronate treatment showed sustained gains in BMD at the lumbar spine and hip compared to baseline.31


An additional target for the medical management of PHPT is the modulation of calcium homeostasis.18


The calcimimetic cinacalcet


is the only therapy approved in Europe for the reduction of hypercalcaemia in patients with PHPT who are unsuitable candidates for PTx, despite meeting clinical criteria.32


As an


allosteric modulator of the calcium-sensing receptor, cinacalcet increases the intracellular calcium concentration, thereby reducing PTH release by the parathyroid gland.33


Cinacalet has


been shown in a placebo-controlled clinical study to achieve long-term reduction in serum calcium and PTH levels in patients with mild PHPT compared with placebo (see Figure 1).34


BMD was


unchanged by cinacalcet; however, serum levels of bone turnover markers increased (p


These results have been Conclusions


Asymptomatic PHPT poses new therapeutic challenges and further research is warranted. Optimal treatment strategies are supported by comprehensive and regularly updated consensus guidelines for both surgical intervention and the increasingly available pharmacological options. n


John Bilezikian is a Professor of Medicine and Pharmacology at the College of Physicians and Surgeons, Columbia University, and Chief of the Division of Endocrinology and Director of the Metabolic Bone Diseases Program at Columbia University Medical Center. His major research interests include the clinical investigation of metabolic bone diseases, particularly osteoporosis and primary hyperparathyroidism. He is Senior Associate Editor of the Journal of Bone and Mineral Research.


Jens Bollerslev is Head of Endocrinology at Rikshospitalet at Oslo University Hospital and Professor of Endocrinology at the University of Oslo. His scientific interests include bone metabolism, monogenetic disorders of bone metabolism and neuroendocrinology, especially acromegaly and growth hormone deficiency. For many years he has been interested in the treatment of borderline primary hyperparathyroidism and he initiated a randomised Scandinavian study on the effect of surgery versus conservative observation. The first results from this study have recently been published.


Claudio Marcocci is an Associate Professor of Endocrinology in the Department of Endocrinology and Metabolism at the University of Pisa and Director of the Unit of Endocrinology and Bone Metabolism at the University Hospital of Pisa. His major research interests are parathyroid and thyroid diseases, particularly primary hyperparathyroidism and Graves’ orbitopathy.


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