Hyperparathyroidism

Hyperparathyroidism is excessive secretion of parathyroid hormone (PTH), and it dysregulates calcium and phosphate homeostasis. It is classified by mechanism into three types, and the treatment of each differs completely.

• Primary HPT - autonomous PTH secretion from a parathyroid adenoma (85%), hyperplasia (10-15%) or, rarely, carcinoma (under 1%)
• Secondary HPT - compensatory PTH elevation in response to chronic hypocalcaemia (renal failure, vitamin D deficiency, malabsorption)
• Tertiary HPT - autonomous PTH secretion developing after prolonged secondary HPT, typically after renal transplant

Why it reaches an orthopaedic surgeon. Hyperparathyroidism causes brown tumours, lytic bone lesions that mimic metastases, as well as pathological fractures and generalised bone loss. In renal failure, secondary HPT leads to renal osteodystrophy, a complex bone disease. Recognising the condition before operating prevents a misdiagnosis of malignancy and guides the choice between medical and surgical management.

What PTH does. PTH raises serum calcium and lowers serum phosphate, acting on bone and at three points in the kidney. Its effect on bone is indirect: it upregulates RANKL through osteoblasts, and RANKL drives the osteoclasts that release calcium from the skeleton.

Primary HPT: adenoma or hyperplasia. An adenoma is a single enlarged gland, usually an inferior one, that has lost normal calcium-sensing feedback and secretes PTH autonomously whatever the calcium level. Removing that gland by targeted adenomectomy cures it. Hyperplasia involves multiple glands (all four) and is associated with the MEN syndromes (MEN1, MEN2A); it needs subtotal or total parathyroidectomy, and familial hypocalciuric hypercalcaemia is its differential.

Secondary HPT. Chronic hypocalcaemia stimulates the parathyroid glands to increase PTH secretion. The calcium is therefore normal or low with a raised PTH, and the PTH rise is an appropriate response. The causes:

• Chronic kidney disease (most common) - reduced phosphate excretion and impaired 1-alpha hydroxylase, so active vitamin D is low
• Vitamin D deficiency - reduced intestinal calcium absorption
• Malabsorption (coeliac disease, Crohn's) - inadequate calcium absorption
• Chronic loop diuretic use - renal calcium wasting

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Tertiary HPT. After prolonged secondary HPT the glands become autonomous and no longer respond to calcium feedback. The typical patient has had a renal transplant, had a high PTH before it, and becomes hypercalcaemic afterwards because the glands go on secreting PTH. Medical management is ineffective and parathyroidectomy is required.

Asymptomatic disease is the most common presentation today. Most cases are detected incidentally on routine automated chemistry panels, often during health screening, rather than through symptoms. The typical finding is a mildly elevated calcium (2.6-2.8 mmol/L) with PTH at 1.5-2 times the upper limit of normal and no bone or renal symptoms. These patients are assessed against the surgical indications and, if they meet none, monitored (see Management).

Symptomatic disease. 20-30% present with symptoms. The classic triad is bones, stones and groans, and the symptoms fall into four groups:

• Skeletal - bone pain (diffuse, worse on weight-bearing), pathological fractures, osteitis fibrosa cystica, brown tumours (jaw, ribs, pelvis, long bones), subperiosteal resorption, and osteoporosis with accelerated bone loss and increased fracture risk
• Renal - nephrolithiasis (20% of patients; calcium oxalate or calcium phosphate stones from hypercalciuria), nephrocalcinosis (calcium deposition in the renal parenchyma), and polyuria and polydipsia from the hypercalcaemia
• Gastrointestinal - abdominal pain, constipation, nausea and vomiting; peptic ulcer disease (a historical association); pancreatitis (rare)
• Neuropsychiatric - fatigue, weakness, depression, anxiety, emotional lability, cognitive impairment, and confusion if hypercalcaemia is severe

Skeletal and renal disease of this kind justifies surgery. Neuropsychiatric symptoms on their own are a weak indication (see Controversies).

Brown Tumours

What they are. Brown tumours are osteoclastic giant cell lesions (osteitis fibrosa cystica) that appear as lytic bone lesions. Excess PTH drives osteoclast activity, and focal areas of resorbed bone are replaced by fibrous tissue and giant cells. Haemorrhage within the lesion leaves haemosiderin, which makes it brown to the naked eye. They are benign reactive lesions, not malignant despite the name, and they resolve after parathyroidectomy.

How they present. On radiographs they are lytic, expansile lesions that mimic metastases, myeloma and giant cell tumour. The commonest sites are the jaw (mandible), ribs, pelvis and long bones. They are usually painless unless a pathological fracture occurs, and may present as a palpable bony swelling.

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Algorithm

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Primary Hyperparathyroidism

When to operate. The criteria below are the indications for parathyroidectomy; a patient with mild asymptomatic disease who meets none can be observed with monitoring. The table is shaped by the Fourth International Workshop (2014) thresholds, which the Fifth Workshop revised in 2022, most substantially the renal criteria, so check any figure against the newer statement (see Evidence Base).

Minimally invasive parathyroidectomy. When imaging localises a single adenoma and sestamibi and ultrasound are concordant, this is now the preferred operation. The adenoma is removed through a 2-3 cm incision, and intraoperative PTH monitoring confirms cure (see the next section); recovery is faster and morbidity lower. The cure rate was 99.4% in the 1,037 minimally invasive cases of Udelsman's single-surgeon series, a very-high-volume ceiling rather than a typical figure.

Bilateral neck exploration. All four glands are visualised and the abnormal ones removed. It is more invasive but comprehensive, and its cure rate in the same series was 97.1%. Hyperplasia is treated by subtotal parathyroidectomy (3.5 glands) or total parathyroidectomy with autotransplantation. The indications:

• Negative or discordant imaging
• Suspected hyperplasia (MEN syndromes)
• Reoperative surgery
• Parathyroid carcinoma

Observation. An asymptomatic patient who does not meet the surgical criteria is monitored with serum calcium every 6-12 months, eGFR annually and DEXA every 1-2 years, adding a 24-hour urine calcium if nephrolithiasis develops. Alongside monitoring:

• Adequate hydration (2-3 L/day)
• Avoid thiazide diuretics, which increase calcium
• Maintain vitamin D sufficiency (25-OH vitamin D 50-75 nmol/L)
• Weight-bearing exercise

Drugs, if surgery is declined. Calcimimetics such as cinacalcet activate the calcium-sensing receptor and lower PTH and calcium. Bisphosphonates prevent bone loss but do not treat the hypercalcaemia. Neither is curative; they control symptoms only.

Secondary Hyperparathyroidism

Treat the cause. In CKD that means phosphate binders, activated vitamin D (calcitriol) and calcimimetics. Vitamin D deficiency is treated with cholecalciferol, 50,000 IU weekly until replete, and malabsorption by treating the gastrointestinal condition and giving oral or intravenous calcium and vitamin D.

Renal osteodystrophy. Management aims for:

• Phosphate under 1.5 mmol/L, with binders
• Calcium 2.2-2.5 mmol/L
• PTH suppressed to 2-9 times the upper limit of normal for the CKD stage
• Monitor for vascular calcification

Why it works. Intact PTH has a circulating half-life of roughly 2 to 4 minutes because the liver and kidney clear it rapidly. Once the last hyperfunctioning gland is removed, the previously suppressed normal glands cannot yet respond, so serum PTH falls steeply within minutes. That kinetic property makes real-time confirmation of cure possible, and it is the enabling technology behind focused, minimally invasive parathyroidectomy.

In practice. A baseline sample is drawn before incision and again just before the adenoma pedicle is clamped; manipulation can transiently spike PTH, so the higher value is the reference. Further samples follow at 5 and 10 minutes after excision. An adequate decay by the Miami criterion confirms that all hyperfunctioning tissue has gone, and the operation can be finished through the small targeted incision.

When PTH fails to fall. An inadequate drop signals residual hyperfunctioning tissue, most often multigland disease (hyperplasia, double adenoma, or a missed or ectopic gland), and mandates conversion to bilateral four-gland exploration. The test is not infallible. A false-positive drop can arise in multigland disease when one dominant gland is removed and another is missed; a false-negative, a persistently high PTH despite cure, can follow difficult gland manipulation or slow clearance in renal impairment.

Mechanism. Hungry bone syndrome (HBS) is the orthopaedically important metabolic pitfall of the immediate post-parathyroidectomy period. Chronic PTH excess drives a high-turnover state in which osteoclastic resorption dominates. When parathyroidectomy removes the PTH abruptly, osteoblastic bone formation is suddenly unopposed, and the demineralised skeleton avidly remineralises, drawing large amounts of calcium, phosphate and magnesium out of the circulation.

Definition. The result is a profound, prolonged hypocalcaemia, classically a serum calcium below 2.1 mmol/L persisting for more than 3 to 4 days after surgery, accompanied by hypophosphataemia and hypomagnesaemia.

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Telling it from hypoparathyroidism. Both cause postoperative hypocalcaemia, and phosphate and PTH separate them. In HBS the calcium is going into bone, so PTH is detectable or even appropriately high and phosphate is low. In hypoparathyroidism, from inadvertent removal or devascularisation of the normal glands, PTH is low or undetectable and phosphate is high. Persistent true hypoparathyroidism is covered in its own topic.

Who is at risk. Markedly elevated preoperative PTH, a high preoperative alkaline phosphatase (a marker of bone turnover), a large adenoma, older age, radiographic osteitis fibrosa cystica or brown tumours, vitamin D deficiency, and renal impairment. Secondary and tertiary HPT carry the highest risk.

Management. Calcium, active vitamin D and magnesium are the treatment:

• Anticipate it in high-risk patients and monitor calcium closely, at least daily at first and often several times a day
• Replete calcium aggressively: intravenous calcium gluconate for symptomatic or severe hypocalcaemia, then high-dose oral calcium
• Give active vitamin D (calcitriol or alfacalcidol) to enhance intestinal calcium absorption and support remineralisation
• Correct magnesium, because hypomagnesaemia impairs PTH secretion and action and perpetuates the hypocalcaemia
• Repletion may be needed for weeks to months, until the skeletal calcium deficit is filled

Prevention. Correct vitamin D deficiency before surgery. In very high-turnover disease some centres give a preoperative bisphosphonate to blunt the postoperative calcium flux.

Global Epidemiology

• Prevalence approximately 1-7 per 1000 adults; among the most common endocrine disorders after diabetes and thyroid disease.
• Female predominance roughly 3:1, peaking in postmenopausal women (age 50-70).
• In high-income settings with routine biochemistry screening, most cases are asymptomatic and detected incidentally; in regions where calcium is not measured routinely, patients still present late with florid skeletal disease (brown tumours, fractures) and renal stones, so the classic "bones, stones, groans" picture remains common.
• Secondary HPT prevalence tracks the burden of chronic kidney disease and vitamin D deficiency, which is high across much of South Asia, the Middle East and parts of Africa.

Side-by-Side Guideline Comparison

Registry and Outcome Notes

• There is no implant registry for parathyroid surgery; outcome benchmarks come from national audit and high-volume series (cure rates 95-99%, permanent hypoparathyroidism and recurrent laryngeal nerve injury each typically under 1-3%).
• Surgeon and centre volume are the strongest determinants of cure and complication rates — a recurring theme across health systems.

High- vs Limited-Resource Practice Variation

• Well-resourced settings: incidental biochemical diagnosis, dual-modality localisation (sestamibi plus ultrasound, with 4D-CT for reoperation), minimally invasive parathyroidectomy with rapid intraoperative PTH, and day-case surgery.
• Limited-resource settings: later presentation with overt bone disease; localisation may rely on ultrasound alone; bilateral neck exploration remains a robust default when rapid PTH assays or nuclear imaging are unavailable; vitamin D repletion before surgery is essential to limit hungry bone syndrome.

Normocalcaemic primary HPT. Some patients have a consistently elevated PTH with a persistently normal calcium once vitamin D deficiency, renal impairment and drugs have been excluded. Whether and when to operate is unresolved, and a proportion progress to classic hypercalcaemic disease.

Surgery for mild or asymptomatic disease. The SIPH randomised trial shows a bone density benefit from surgery, but no randomised trial has yet shown fewer fractures in mild disease. The threshold for operating on patients who do not meet formal criteria therefore remains debated.

Non-classical (neurocognitive) symptoms. Fatigue, low mood and cognitive complaints are common, but improvement after parathyroidectomy is inconsistent across studies. Alone, they are a weak indication for surgery.

Localisation strategy. The best first-line imaging (ultrasound, sestamibi-SPECT, 4D-CT or choline PET) varies with availability and expertise. Negative imaging does NOT exclude an adenoma and should not deny a patient surgery by an experienced surgeon.

Bilateral exploration or focused surgery. Focused surgery risks missing multigland disease. Intraoperative PTH monitoring reduces that risk without eliminating it, and some centres still favour four-gland assessment.

The place of cinacalcet. It lowers calcium but does not reliably improve bone density or cure the disease. It is reserved for patients unfit for or declining surgery, not offered as an equivalent alternative.