Surgery represents the only potential definitive/curative treatment for primary hyperparathyroidism. Parathyroidectomy, like all surgery, is associated with some risks, but morbidity is relatively low and the success rate in the hands of an experienced parathyroid surgeon is excellent (95-98% cure). Patients not undergoing parathyroidectomy may be observed or receive medications. Medical treatment is focused on lowering calcium and/or PTH levels and ameliorating some of the adverse bone outcomes associated with hyperparathyroidism.
Parathyroid Surgery – Patient selection
As the only definitive treatment, surgery remains an option for all patients with primary hyperparathyroidism, and a discussion of the risks, potential benefits, and alternative should be provided to each patient individually.
Patients with symptomatic primary hyperparathyroidism have a clear indication to favor surgical management. Patients are considered symptomatic if they have had a clinically apparent kidney stone, have significant bone manifestations (fragility fractures or osteitis fibrosa cystica) or have had a hypercalcemic crisis. Osteitis Fibrosa Cystica is a rare manifestation of hyperparathyroidism in the developed world. It is characterized by low bone density, bone cysts and brown tumors, and an increased propensity for pathologic fractures. It is a late manifestation of hyperparathyroidism that was more commonly seen prior to the availability of serum calcium measurements. A hypercalcemic crisis is characterized by “dangerously” high levels of serum calcium typically requiring hospitalization for intravenous fluids and medications to lower the calcium level.
Patients not meeting the above criteria are considered “asymptomatic”, despite the fact that many may report neurocognitive symptoms potentially associated with hyperparathyroidism. The International Workshop on Asymptomatic Primary Hyperparathyroidism has published consensus guidelines suggesting appropriate surgical indications in these patients. The most recent guidelines, arising out of the 4th international workshop were published in 2014. In these guidelines, surgery is advised in symptomatic patients with:
1. Elevation in serum calcium more than 1.0 mg/dL above the upper limit of the normal range
2. Significant bone manifestations defined as:
a. Bone mineral density T score <-2.5 at the spine, hip or distal radius
b. Vertebral fractures noted on imaging
3. Significant renal effects or risk defined as:
a. Asymptomatic kidney stones noted on imaging
b. Reduced kidney function (creatinine clearance <60ml/min)
c. 24-hour urine calcium >400mg, in conjunction with a high-risk biochemical stone analysis
d. Nephrocalcinosis (calcification of the kidney) on imaging
4. Age <50 years
Patients who do not meet the above criteria may still wish to pursue surgical management. Those with significant neurocognitive symptoms may experience some improvement in these symptoms post-operatively, although this is not perfectly predictable. Management of these patients should be individualised and involve a long discussion of the risks, benefits, and alternatives to surgery.
Benefits of parathyroidectomy
The goal of parathyroidectomy is to achieve a biochemical cure and prevent or reverse some of the signs and symptoms of primary hyperparathyroidism. Potential benefits of surgery in primary hyperparathyroidism include:
1. Improved bone health: Over time, hyperparathyroidism results in loss of bone density and increased risk of fractures when compared to the general population. Following successful surgery, patients may see an increase in bone mineral density of up to 8-12%. This increased bone density may be observed at the spine, hip and radius (three sites typically evaluated in primary hyperparathyroidism). In addition, this benefit appears to be durable, persisting even over follow-up periods of 10–15 years. Perhaps more importantly, these changes in bone health appear to translate to a decrease in fracture risk.
2. Reduced risk of kidney stones: Up to one third of patients with primary hyperparathyroidism will develop kidney stones over time if untreated. Parathyroidectomy is highly effective at reducing the risk of new kidney stones and prevents further stone formation in those already affected.
3. Symptoms affecting quality of life: Symptoms associated with hyperparathyroidism may adversely affect a patient’s quality of life. These include neurocognitive symptoms and bone pain. Several studies have suggested that a large proportion of patients (up to 80%) experience some relief of these symptoms. Unfortunately, there is not a definitive way to predict which patients and symptoms will improve post-operatively.
4. Premature death (and cardiovascular death): Patients with hyperparathyroidism appear to have higher rates of premature all-cause and cardiovascular mortality. Hypertension, left ventricular function, and vascular endothelial function have been studied as they relate to primary hyperparathyroidism. While some literature suggests that earlier surgery may be beneficial in this regard, this issue is in need of further study and clarification.
Non-Surgical Options – Observation
Patients with mild, asymptomatic primary hyperparathyroidism may elect to undergo observation. Typically, this involves regular laboratory studies (every 6 months) including calcium and PTH levels, regular bone mineral density assessment (2-year intervals), and clinical assessment to monitor for the development of kidney stones or worsening symptoms. During observation, if patients develop a stronger indication for surgery, this option can be revisited. Previous series of patients followed with observation suggest that over a 10–15 year period, 1/4 to just over 1/3 of patients will develop a stronger indication for surgery.
Bone mineral density in patients undergoing observation tends to remain stable in the short term. However, after 8 years of observation, reductions in bone density at the hip and distal radius have been noted. Recall that this is in comparison to increased bone mineral density in those that have had surgery. In addition, fracture risk may be higher in those undergoing observation compared with post-surgery patients. While patients presenting without kidney stones appear to be at low risk of developing new stones, those that have a history of stones and elect observation are at high risk of continuing to form stones. Further clarification on risk of cardiovascular events, premature death, and neurocognitive symptoms is required but could potentially be more frequent with observation.
Non-Surgical Options – Medical Management
A number of medical options have been explored in patients not pursuing surgical treatment due to patient preference or surgical contraindication. Medical options that have been explored include:
- Bisphosphonates (e.g., alendronate)
- Hormone replacement therapy (post-menopausal women)
- Calcimimetics (e.g., cinacalcet)
Given the prominent bone health implications of primary hyperparathyroidism and the potential significant impact of increased fracture risk in an aging group of patients, the motivation to examine bisphosphonates is intuitive. These medications reduce osteoclast activity resulting in lower bone turnover. Several studies have been done, and most of these have examined the commonly used drug alendronate. This medication appears to have beneficial effects on bone mineral density at the hip and spine with a concomitant reduction in bone turnover markers. The medication does not appear to have a significant effect in lowering serum calcium or PTH levels. In addition, these studies do not include long-term followup, so the durability of these effects is unclear. As well, bisphosphonates, like all medications, have potential side effects including rare but serious osteonecrosis of the jaw and severe esophagitis.
Hormone replacement therapy has been shown to have some beneficial effects on bone health in post-menopausal women. As such, it bears promise for the medical treatment of post-menopausal women with primary hyperparathyroidism and reduced bone density. Treatment with estrogen appears to increase bone mineral density at the hip and spine over short-term followup (2 years). No data exist to demonstrate a reduction in fracture risk. Similarly, evidence on selective estrogen receptor modulators, such as raloxifene, is not sufficient to draw any specific conclusions. Hormone therapy has not been shown to impact serum calcium or PTH.
Calcimimetic medications (e.g., cinacalcet) reduce PTH production and secretion by binding to the calcium sensing receptor. The use of this medication in patients with primary hyperparathyroidism results in reductions in serum calcium and normalization of phosphate. No significant effects on bone density or fracture risk have been noted. Side effects my limit patient compliance in about 1/5th of patients. Side effects may include nausea and vomiting, adynamic bone disease, and worsening heart and liver function. In addition, the medication is quite expensive, estimated at over $7,000 per year. Given this, it is most commonly used in patients with symptomatic hypercalcemia who are not able to undergo parathyroidectomy (i.e., due to surgical risks, surgical failure after multiple procedures, or incurable parathyroid cancer). Given its serum calcium effects, some interest has been shown in combining the potentially synergistic effects of calcimimetics and bisphosphonates.