Hyperparathyroidism Management

The goal of pharmacological therapy is to normalize calcium levels. This is recommended for the following individuals: Mildly elevated serum calcium levels (<1 mg/dL above the upper normal limit), no previous life-threatening hypercalcemic episodes, normal bone and renal status, clinically asymptomatic, individual >50 years old, poor surgical candidate, refusal to undergo surgery, and patient preference. Pharmacological therapy may be started before or after surgery.  

Bisphosphonates 

Hyperparathyroidism_Management 1

Example drugs: Aledronate, Pamidronate, Risedronate  

Biphosphonates are potent inhibitors of bone resorption and improve bone mineral density. This is recommended for patients with primary hyperparathyroidism and osteoporosis or those with low bone mineral density warranting intervention who opted not to undergo surgery. This is an alternative treatment for mild hypercalcemia due to primary hyperparathyroidism. A randomized placebo-controlled clinical trial showed significant increases in bone mineral density in the lumbar spine, hip, and femoral neck in addition to marked reductions in bone turnover markers after 2 years of treatment with Aledronate. Pamidronate is most effective for acute treatment of hypercalcemia associated with primary hyperparathyroidism. 

Calcimimetic  

Calcimimetics inhibit parathyroid hormone secretion by activating calcium-sensing receptors in the parathyroid gland. This is used for poor surgical candidates to normalize serum calcium in patients with severe hypercalcemia. This is preferred over bisphosphonates for patients who are unable to have surgery and whose primary indication for surgery is symptomatic and/or severe hypercalcemia with normal bone density. 

Cinacalcet  

Cinacalcet is approved for use in primary hyperparathyroidism. This is the only approved calcimimetic for secondary hyperparathyroidism treatment. This is used to treat hyperparathyroidism in end-stage renal disease patients on long-term dialysis. Oral administration peaks within 2-3 hours, which lowers circulating parathyroid hormone levels within the same period. This reduces serum calcium levels in PTCA patients, particularly in unresectable diseases and those who underwent multiple operations without cure.  

Vitamin D and Analogues 

Hyperparathyroidism_Management 2

Aggressive supplementation is recommended for secondary hyperparathyroidism patients due to vitamin D deficiency with normal renal function. This helps in the suppression of parathyroid hormone secretion and inhibits the evolution of parathyroid hyperplasia. Adequate daily intakes of 200 IU, 400 IU, and 600 IU of vitamin D are recommended for adults up to 50 years, 51-70 years, and ≥71 years, respectively. For patients with vitamin D deficiency, 50,000 IU weekly for 8 weeks or 3,000 IU daily of vitamin D2 supplementation or 1,000 IU of daily vitamin D3 is recommended. Caution must be observed, as high doses can lead to hypercalcemia. Vitamin D analogues (Paricalcitol and Doxercalciferol) are less likely to cause hypercalcemia. 

Other Drugs  

Denosumab may be an antiresorptive option for primary hyperparathyroidism, as shown in a retrospective longitudinal study wherein women with primary hyperparathyroidism showed greater bone mass gain than those with osteoporosis after 2 years on Denosumab. Hormone replacement therapy has been shown to improve bone mineral density, suppress bone turnover, and reduce calciuria in postmenopausal women with asymptomatic primary hyperparathyroidism.  

Surgery is a definitive treatment for patients with hyperparathyroidism. This is recommended but not mandatory for those who are asymptomatic without disease progression. Parathyroidectomy cures the disease, decreases the risk of kidney stones, improves bone mineral density, may decrease fracture risk, and improves quality of life. 

Indications

• Symptomatic primary hyperparathyroidism as defined by the presence of renal and bone involvement 
• Asymptomatic primary hyperparathyroidism if any one of the following is present: Threshold value of serum calcium >1 mg/dL (>0.25 mmol/L) above the upper normal limit; a bone density T-score of ≤-2.5 at the lumbar spine, femoral neck, total hip or distal ⅓ radius; presence of vertebral fracture by X-ray or VFA with or without prior documentation; eGFR <60 mL/min/1.73 m²; creatinine clearance of <60 cc/min; increased calcium-containing stone risk and marked hypercalciuria; radiologic evidence of nephrocalcinosis or renal stones; 24-hour urinary calcium >250 mg/day (6.25 mmol/day) in women and >300 mg/day (7.5 mmol/day) in men; and age <50 years old.  
• Secondary hyperparathyroidism that is refractory to medical therapy, with PTH >1,000 pg/mL, calcium x phosphorus product >55, renal osteodystrophy, calciphylaxis, and other retractable symptoms (eg uremic pruritus, persistent anemia, bone pain, muscle pain, abdominal pain, fatigue, weakness) 
• Tertiary hyperparathyroidism presenting with severe hypercalcemia (calcium >12.5 mg/dL), persistent hypercalcemia ≥2 years after renal transplantation (with decline in renal function and without graft rejection), nephrolithiasis, progressive bone disease, pancreatitis 

Contraindications  

Contraindications for surgery are lack of confirmation of diagnosis for persistent or recurrent primary hyperparathyroidism and inconclusive localization studies, which may lead to blind exploration.

Preoperative Management  

Preoperative management includes daily intake of 1,000-1,200 mg of calcium which is recommended for adults and primary hyperparathyroidism patients; preoperative vitamin D repletion is advised but must be done with caution in patients with hypercalciuria; and preoperative voice evaluation includes specific injury involving subjective and significant voice changes or prior at-risk surgery history. 

Surgical Techniques  

Bilateral Neck Exploration 

Hyperparathyroidism_Management 3

Bilateral neck exploration is a standard surgical approach for most patients with primary hyperparathyroidism. This has a long-term success rate of >95% with low rates of complications. This relies on visual and weight-based estimations of gland size to distinguish a single adenoma from multi-glandular disease. This is a preferred surgical technique in cases of discordant or non-localizing preoperative imaging and is suggested in cases of residual hyper-secreting tissue.  

Minimally Invasive Parathyroidectomy  

Minimally invasive parathyroidectomy achieves a 97-99% cure rate when done with intraoperative parathyroid hormone measurement to confirm resection adequacy. The advantages include limited dissection, faster recovery, decreased postoperative discomfort, and shorter incision length. Preoperative imaging and other adjuncts are required prior to the procedure. Indications include a patient with a high probability of solitary parathyroid adenoma with a significant uptake on sestamibi scintigraphy; absence of thyroid nodules showing sestamibi uptake; absence of familial hyperparathyroidism or MEN history; absence of neck irradiation; and re-operation for persistent or recurrent hyperparathyroidism and ectopic adenoma. 

Gamma-probe Guided Surgery  

Gamma-probe guided surgery is more sensitive than gamma camera. This provides an easier surgical approach, shorter operation time, verification of the correct excision of the pathological tissue and success of surgery. This is indicated for patients undergoing bilateral neck exploration with negative preoperative scintigraphy and may be performed using a minimally invasive approach or through bilateral cervical exploration. 

Concurrent Thyroidectomy  

Concurrent thyroidectomy is performed in patients with thyroid disease requiring resection, sporadic parathyroid cancer suspect, abnormal intrathyroid parathyroid gland removal or access improvement, and concomitant thyroid disease during parathyroidectomy for primary hyperparathyroidism with isolated thyroid disease.  

Immediate Postoperative Management 

Monitor patients for complications (eg bleeding, hypocalcemia, vocal cord paralysis, laryngospasm). Check if the serum calcium concentration reaches nadir within 24-36 hours post-surgery and if the serum parathyroid hormone level is in the normal range within 30 hours post-surgery. Maintain a low-calcium diet until normal serum calcium concentration is achieved. Seizure precautions should be observed at all times. “Hungry bone syndrome” may develop in patients with large adenomas postoperatively. This is associated with hypocalcemia, hypophosphatemia, and low urinary calcium excretion. Persistent hypercalcemia and elevated parathyroid hormone levels post-surgery may indicate surgical failure. 

Surgical Adjuncts  

Confirmation of Resected Parathyroid Tissue  

Confirmation of resected parathyroid tissue is done by frozen section analysis and ex vivo parathyroid aspiration.  

Gland Visualization  

Gland visualization is done by methylene blue, near-infrared fluorescence and infrared spectroscopy.  

Gland Localization  

Gland localization is done by intraoperative ultrasonography, bilateral jugular venous sampling, and gamma-probe guidance. 

Intraoperative Rapid Parathyroid Hormone (PTH) Test  

Intraoperative rapid parathyroid hormone test is performed in minutes to detect any remaining abnormal glands, which provides real-time parathyroid function assessment. Terminate the surgery if there is >50% fall in intraoperative parathyroid hormone levels. Full neck exploration may be necessary if there is <50% fall in intraoperative parathyroid hormone levels to look for other hyperactive glands and ectopic parathyroid glands (usually found in intrathyroid, retroesophageal, or mediastinal location). 

Preventive Measures  

Preventive measures are recommended for patients with comorbidities, contraindications to surgery, prior unsuccessful neck explorations that preclude ѕurgеry, or those who refuse ѕurgеrу. Avoid hypercalcemia-aggravating factors. Encourage physical activity to minimize bone resorption. Adequate hydration is encouraged to minimize nephrolithiasis risk. Moderate calcium intake (1,000 mg/day) should be maintained. Moderate calcium restriction (<800 mg/day) is warranted in patients with high serum calcitriol concentration. Maintain moderate vitamin D intake (400-800 IU 24 hourly) to maintain a 25-(OH)-D level of at least 20 or 30 ng/mL (50 or 75 mmol/L). Restriction of dietary phosphorus and correction of hyperphosphatemia in patients with secondary hyperparathyroidism.