Clinical Endocrinology

When would I use medical therapies for the treatment of primary hyperparathyroidism?

Authors

  • Rachel K. Crowley,

    1. Department of Endocrinology, University Hospital Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK
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  • Neil J. Gittoes

    Corresponding author
    1. Department of Endocrinology, University Hospital Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK
    • Correspondence: Dr Neil Gittoes, Department of Medicine, Old Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK. E-mail: Neil.Gittoes@uhb.nhs.uk

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Summary

Although there may be controversy surrounding the indications for parathyroidectomy in primary hyperparathyroidism, it remains the only accepted definitive therapy. However, even if parathyroidectomy is indicated, some patients refuse surgery, are medically unfit or have residual or recurrent disease inaccessible to further surgery. Some of these patients may be suitable for long-term observation but others require intervention for management of symptomatic or moderate to severe hypercalcaemia, loss of bone mineral density or renal calculi. The selection of a suitable therapy for each patient should be individualized.

When should I consider medical management of primary hyperthyroidism?

Primary hyperparathyroidism (PHPT) is defined as hypercalcaemia in the presence of high or inappropriately normal parathyroid hormone (PTH) levels.[1, 2] Familial hypocalciuric hypercalcaemia should be considered within the differential diagnosis and excluded accordingly.[3] PHPT has a prevalence of up to 5% in certain populations[4], and rates of diagnosis have been increasing since the introduction of automated biochemistry analysers.[2, 4] Surgery is the primary management modality for treatment of PHPT[5] – but the increase in numbers of patients with mild disease means that three distinct PHPT cohorts now attend metabolic bone clinics: patients with symptomatic PHPT and/or evidence of end-organ disease who should be referred for surgery; patients with symptomatic PHPT who meet criteria for surgical intervention but who do not have surgery because they refuse or are unfit; and those who have mild asymptomatic disease that do not meet current recommendations for surgery who are often observed over time and offered intervention at a later stage if necessary.

A consensus on the indications for surgery was established at the Third International Workshop on PHPT[5] and are summarized in Table 1. The consensus guidelines have been widely adopted into international practice but are based on clinical practice in the United States and remain controversial, particularly with regard to the serum calcium recommendations (see Table 1).[4] Patients who meet these criteria but are not referred for surgery include those who are not fit for surgery or anaesthetic, who refuse surgery or who have failed previous intervention; these are the patients who may require medical intervention.[6] Medical therapies may also be of benefit for those who are awaiting surgery, and women in the first or third trimesters of pregnancy (parathyroidectomy may be performed in the second trimester).[7] A recent study reported use of medical therapy for patients who did not have positive localization of an adenoma at preoperative imaging;[8] this probably reflects the practice described in a survey of endocrine surgeons, 38% of whom would not offer surgery to a patient with PHPT and mild nonspecific symptoms if the pre-operative sestamibi scan were negative.[9] However, the authors propose that negative pre-operative imaging is not an absolute indication for deferring surgery; instead, bilateral neck exploration should be considered;[10] if the patient does not meet criteria for surgery it is reasonable to forego imaging and observe without specific medical treatment.

Table 1. Indications for surgery in asymptomatic PHPT[5]
ParameterMeasurement
Serum calcium>0·25 mm above the upper limit of normal
Creatinine clearance<60 ml/min
Bone mineral densityT score <−2·5 at any site or previous fragility fracture
Age<50 years old

The consensus on the indications for surgery was based on the evidence of benefit from lowering PTH and calcium levels via parathyroidectomy; in the absence of symptoms this evidence is most robust for improvement in bone mineral density. It seems reasonable that medical therapy should be considered where the indications for parathyroidectomy have been met but the patient will not or cannot have surgery; these would include hypercalcaemia (corrected calcium >2·85 or 0·25 mm greater than the upper limit of the local reference range), metabolic bone disease and management of nephrolithiasis.

What is the optimal medical intervention for hypercalcaemia in PHPT?

Symptomatic hypercalcaemia usually occurs when serum calcium is particularly high (usually >3·0 mm) or when there has been an acute elevation in calcium levels (e.g. in the setting of acute dehydration); such symptoms include fatigue, change in cognitive status, nausea, constipation and thirst. Neuropsychiatric and quality of life-related symptoms of hypercalcaemia are not currently considered indications for parathyroidectomy or medical therapy.[4, 5] Serum calcium should be measured yearly in patients with asymptomatic primary hyperparathyroidism who do not undergo surgery[11] and serum total calcium measurements should be corrected for serum albumin.[12] Patients who are known to have PHPT should avoid dehydration, thiazide diuretics and lithium therapy where possible, and should be advised to maintain dietary calcium intake and vitamin D levels.[2, 13]

Patients in whom the serum calcium at presentation, or at follow-up, is >0·25 mm above the local reference range should be referred for surgery and if this is not feasible, could be considered for therapy with a calcimimetic if symptomatic and in the setting of normal vitamin D (see Table 2).[6] Calcimimetics act at the calcium sensing receptor to reduce synthesis and secretion of PTH with consequent lowering of serum calcium.[13] Cinacalcet was granted a marketing authorization in Europe and the United States in 2004, initially for management of secondary hyperparathyroidism in renal failure and for management of hypercalcaemia in parathyroid carcinoma. It was later approved for use in patients with primary hyperparathyroidism, who meet hypercalcaemia criteria for parathyroidectomy but do not undergo surgery. The licence for cinacalcet recommends a starting dose of 30 mg bd for hypercalcaemia in primary hyperparathyroidism but in a recent Italian review of its use, in which patients were included who had mild hypercalcaemia, calcium improved at 30 mg od.[8] In a small study of patients with PHPT and serum calcium >3·1 mmol, 53% of patients had normal serum calcium and 88% had a reduction of >0·25 mm after titration of cinacalcet.[14] The effect of cinacalcet on hypercalcaemia appears to persist for at least 4 years, in spite of the fact that PTH levels do not normalize.[15] BMD does not increase with cinacalcet treatment; it should not be used to manage low BMD in patients with milder elevations of serum calcium (see Table 2).[16] It has been suggested that a trial of short-term cinacalcet to lower serum calcium may be used in older patients with cognitive impairment to assess the potential cognitive benefit of calcium correction when considering parathyroidectomy.[13] This is controversial, however, and would be best explored further with an appropriate clinical trial. An American review of cinacalcet use in asymptomatic PHPT suggested that it was not cost effective at current US costings; with cost in mind the authors are aware that many UK centres use cinacalcet in PHPT only when serum calcium exceeds 3·0 mm[17].

Table 2. Outcomes for medical therapy in PHPT
Medical TherapyPotential benefit in PHPT
Cinacalcet

Effective in lowering serum calcium Relief of symptoms associated with hypercalcaemia

No benefit demonstrated for bone density or for prevention of nephrolithiasis

Bisphosphonate

Improvement in BMD at hip and spine, and bone turnover

Transient reduction in serum calcium is not sustained

No reduction in fracture risk demonstrated

Oestrogen

Improvement in BMD

No sustained reduction in serum calcium or PTH

RaloxifeneImprovement in BMD

How could I prevent bone loss in PHPT?

Mild PHPT is associated with increased risk of fracture, with a hazard ratio of 1·75,[18] and was the most common cause of low bone density after vitamin D deficiency in a recent study of ‘primary’ osteoporosis.[19] There are some features of bone mineral density in PHPT that distinguish it from bone loss secondary to other metabolic bone diseases;[20] PHPT-related bone loss is diffuse but is often most marked when measured at the distal radius, and the rate of bone loss in PHPT is slightly faster than age-associated bone loss in the background population.

Bone loss associated with PHPT is exacerbated by co-existing vitamin D deficiency; in PHPT subjects with vitamin D levels <25 nm, BMD is lower at the hip, lumbar spine and forearm sites on DXA measurement.[21] There is no guideline for diagnosis of vitamin D deficiency in PHPT but the Institute of Medicine and the recent UK Vitamin D Guidelines (http://www.nos.org.uk/document.doc?id=1352) regard 50 nm as vitamin D replete in the general population. Replacement of vitamin D in deficient patients may unmask previously unrecognized PHPT[19]; in known PHPT patients with vitamin D deficiency, replacement with high and low dose vitamin D regimens is not associated with a rise in serum calcium (see graph in Wagner et al[22]) or increased incidence of nephrolithiasis.[22, 23] The authors’ practice is to replace vitamin D with an oral D3 preparation of 800 IU/day that does not contain calcium, and to measure serum calcium during and after vitamin D replacement.[20] Axial BMD does not improve in PHPT after vitamin D replacement.[23] Replacement of vitamin D in those PHPT patients who are awaiting surgery is widely recommended to prevent hungry bone syndrome in the postoperative period, although the evidence for this remains inconclusive.[4, 24]

Bisphosphonate use in postmenopausal women with PHPT was associated with an improvement in BMD and bone turnover but the short duration of studies conducted with alendronate (1–2 years) have not demonstrated reduction in fracture risk.[25-27] Over 2 years of follow-up, oral alendronate appears to be equivalent to parathyroidectomy in terms of BMD increase (see Table 2).[27] In postmenopausal women with PHPT, oestrogen may be beneficial, where indicated for management of menopausal symptoms[6, 20], but neither oestrogen nor raloxifene are first line medical therapies in the management of low BMD associated with PHPT. In a small study, raloxifene use was associated with a reduction in serum calcium and in bone turnover (see Table 2).[28] There is some evidence that oestrogen may act at oestrogen receptor subtypes (ERβ1) as a tumour suppressor in parathyroid adenomas[29] which would be an added benefit to the use of oestrogen, as well as its antiresorptive effects, in a suitable PHPT population.

Could I prevent the development of nephrolithiasis in PHPT?

The prevalence of nephrolithiasis in PHPT varies between 10 and 30%, according to the case-finding methods employed in a number of series[30-32] and stone formation is a risk in PHPT patients with normal as well as high serum calcium.[30] Male gender appears to be associated with stone formation in PHPT[33], but it is not possible to identify individual patients with PHPT who are at risk of stone development using biochemical parameters alone[32, 34] and advice about the imaging modality for optimal case-finding is conflicting.[32]

Parathyroidectomy is recommended in PHPT associated with nephrolithiasis. However, patients remain with an increased incidence of renal stones for many years following successful parathyroid resection.[23, 33] Such patients may benefit from medical management, but there is little evidence-base to guide treatment planning.[33] Patients should be advised to maintain good hydration and given dietary advice (reduction of oxalate intake but maintenance of dietary calcium), which may be helpful to some individuals.[13] The use of thiazide diuretics to reduce urinary calcium is not advisable in PHPT patients that do not undergo surgery, because of the potential for dehydration and elevation of serum calcium.[13]

Conclusion

A subset of patients with symptomatic PHPT meets the criteria for parathyroidectomy but cannot or will not undergo surgical intervention; these patients may benefit from medical therapy. Failure to localize a parathyroid adenoma in the pre-operative work-up is not an indication to consider medical therapy; such patients should undergo bilateral neck exploration.

Although calcimimetics provide an appealing theoretical medical ‘solution’ to the consequences of active PHPT, data with cinacalcet have been disappointing with respect to bone and renal end points. Cinacalcet is, however, effective in managing the hypercalcaemia of PHPT. Oestrogen and raloxifene improve bone density in PHPT but should only be used in women with specific adjunctive comorbidites. Bisphosphonates are beneficial in prevention of bone density loss in PHPT but trial design has limited the conclusions that can be drawn regarding fracture risk. No medical therapy has been shown to reduce nephrolithiasis in PHPT.

Conflict of interests/Financial disclosure

Nothing to declare.

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