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Nonsurgical Management of Primary Hyperparathyroidism

  • Author Footnotes
    1 Dr Farford is now at the Keesler Air Force Base, Miss.
    Bryan Farford
    Footnotes
    1 Dr Farford is now at the Keesler Air Force Base, Miss.
    Affiliations
    Department of Family Medicine, Mayo Clinic College of Medicine, Jacksonville, Fla
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  • R. John Presutti
    Correspondence
    Address reprint requests and correspondence to R. John Presutti, DO, Department of Family Medicine, Mayo Clinic College of Medicine, 4500 San Pablo Rd, Jacksonville, FL 32224
    Affiliations
    Department of Family Medicine, Mayo Clinic College of Medicine, Jacksonville, Fla
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  • Author Footnotes
    2 Dr Moraghan is now with the University of North Dakota School of Medicine, Grand Forks.
    Thomas J. Moraghan
    Footnotes
    2 Dr Moraghan is now with the University of North Dakota School of Medicine, Grand Forks.
    Affiliations
    Division of Endocrinology, Mayo Clinic College of Medicine, Jacksonville, Fla
    Search for articles by this author
  • Author Footnotes
    1 Dr Farford is now at the Keesler Air Force Base, Miss.
    2 Dr Moraghan is now with the University of North Dakota School of Medicine, Grand Forks.
      Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting and is typically caused by a single benign parathyroid adenoma. Most patients with hyperparathyroidism are postmenopausal women. Patients can be asymptomatic or minimally symptomatic. Parathyroidectomy is the definitive cure for primary hyperparathyroidism, and no medical therapies have been approved by the Food and Drug Administration for this disorder. Guidelines for surgery have been established by a National Institutes of Health consensus panel, but many patients do not meet these guidelines or have comorbid conditions that prohibit surgery. This review describes alternative treatment options for patients who decide against or are unable to proceed with surgery.
      Primary hyperparathyroidism is a leading cause of hypercalcemia in the outpatient setting. The typical patient is a postmenopausal woman older than 50 years (mean age, 55 years). In the United States, the incidence of primary hyperparathyroidism is 2 to 3 per 1000 women and approximately 1 per 1000 men.
      • Kearns AE
      • Thompson GB
      Medical and surgical management of hyperparathyroidism [published correction appears in Mayo Clin Proc. 2002;77:298].
      • Taniegra ED
      Hyperparathyroidism.
      The diagnosis of primary hyperparathyroidism has increased during the past 30 years with the development and use of automated blood analyzers to monitor serum calcium levels, but the incidence of cases has been declining since the mid 1980s.
      • Wermers RA
      • Khosla S
      • Atkinson EJ
      • Hodgson SF
      • O'Fallon WM
      • Melton III, LJ
      The rise and fall of primary hyperparathyroidism: a population-based study in Rochester, Minnesota, 1965-1992.
      Because of advances in radiographic and surgical techniques, the classic presentation of primary hyperparathyroidism with complications of nephrocalcinosis, nephrolithiasis, and osteitis fibrosa cystica is rare today.
      • Kearns AE
      • Thompson GB
      Medical and surgical management of hyperparathyroidism [published correction appears in Mayo Clin Proc. 2002;77:298].
      • Taniegra ED
      Hyperparathyroidism.
      Findings in patients with primary hyperparathyroidism include persistent hypercalcemia and elevated serum parathyroid hormone (PTH) levels. Malignancy, the second most common cause of hypercalcemia, is distinguished from primary hyperparathyroidism by constantly low or suppressed PTH levels. In rare cases, patients may have higher PTH levels that are attributable to ectopic PTH secretion, coexisting primary hyperparathyroidism, or PTH resistance. Although surgery is the definitive treatment for patients with symptomatic primary hyperparathyroidism, many patients do not meet established surgical criteria or have comorbid conditions that prohibit surgery. This article reviews the management of primary hyperparathyroidism in patients who qualify as surgical candidates but decline or have contraindications to surgery.

      SYMPTOMS OF PRIMARY HYPERPARATHYROIDISM

      A National Institutes of Health consensus panel recognized 2 forms of primary hyperparathyroidism: asymptomatic and symptomatic.
      • Taniegra ED
      Hyperparathyroidism.
      • Bilezikian JP
      • Potts Jr, JT
      • El-Hajj Fuleihan G
      • et al.
      Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century.
      Patients with asymptomatic primary hyperparathyroidism account for 75% to 80% of cases and usually have serum calcium levels that are no more than 1.0 mg/dL higher than the normal range of 8.9 to 10.1 mg/dL; however, these levels may be as high as 12.0 mg/dL in younger healthy patients.
      • Kearns AE
      • Thompson GB
      Medical and surgical management of hyperparathyroidism [published correction appears in Mayo Clin Proc. 2002;77:298].
      • Taniegra ED
      Hyperparathyroidism.

      Fuleihan Gel-H. Clinical manifestations of primary hyperparathyroidism. In: Rose BD, ed. UpToDate Waltham, Ma; 2005.

      • Bilezikian JP
      • Silverberg SJ
      Clinical practice: asymptomatic primary hyperparathyroidism.
      Symptomatic primary hyperparathyroidism has no specific clinical presentation, but several nonspecific symptoms may be found by eliciting a thorough medical history. Patients may have weakness, mild depression, fatigue, anorexia, and often increased absence from work. Patients with symptomatic hyperparathyroidism usually have a serum calcium level higher than 12 mg/dL, and nearly all patients with levels exceeding 14 mg/dL are symptomatic.
      • Kearns AE
      • Thompson GB
      Medical and surgical management of hyperparathyroidism [published correction appears in Mayo Clin Proc. 2002;77:298].
      The signs and symptoms of hyperparathyroidism (Table 1) largely reflect the effects of hypercalcemia and may involve multiple organ systems.
      • Kearns AE
      • Thompson GB
      Medical and surgical management of hyperparathyroidism [published correction appears in Mayo Clin Proc. 2002;77:298].
      • Taniegra ED
      Hyperparathyroidism.
      • Bilezikian JP
      • Potts Jr, JT
      • El-Hajj Fuleihan G
      • et al.
      Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century.

      Fuleihan Gel-H. Clinical manifestations of primary hyperparathyroidism. In: Rose BD, ed. UpToDate Waltham, Ma; 2005.

      TABLE 1Signs and Symptoms of Primary Hyperparathyroidism
      • Kearns AE
      • Thompson GB
      Medical and surgical management of hyperparathyroidism [published correction appears in Mayo Clin Proc. 2002;77:298].
      • Taniegra ED
      Hyperparathyroidism.
      • Bilezikian JP
      • Potts Jr, JT
      • El-Hajj Fuleihan G
      • et al.
      Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century.

      Fuleihan Gel-H. Clinical manifestations of primary hyperparathyroidism. In: Rose BD, ed. UpToDate Waltham, Ma; 2005.

      • Neurologic
        • Inability to concentrate
        • Confusion
        • Depression
        • Anxiety
        • Fatigue
      • Cardiovascular
        • Hypertension
        • Left ventricular hypertrophy
        • Prolonged QT interval
        • Bradycardia
        • Valvular calcification
        • Arrhythmia
      • Gastrointestinal
        • Anorexia
        • Nausea
        • Constipation
        • Vomiting
        • Abdominal pain
        • Pancreatitis
        • Peptic ulcer disease
      • Renal
        • Nephrolithiasis
        • Renal insufficiency
        • Nephrocalcinosis
        • Polydipsia
        • Polyuria
      • Musculoskeletal or rheumatologic
        • Osteopenia
        • Osteoporosis
        • Gout
        • Pseudogout
        • Bone or joint pain
        • Cystic bone lesions
        • Chondrocalcinosis

      TYPES OF PRIMARY HYPERPARATHYROIDISM

      The pathogenesis of sporadic primary hyperparathyroidism involves abnormal tissue in the parathyroid gland. Approximately 80% to 85% of patients with primary hyperparathyroidism have benign parathyroid adenomas, and the remainder have hyperplasia (parathyroid carcinomas are rare, occurring in approximately 1% of cases).
      • Kearns AE
      • Thompson GB
      Medical and surgical management of hyperparathyroidism [published correction appears in Mayo Clin Proc. 2002;77:298].
      • Taniegra ED
      Hyperparathyroidism.
      • Shoback DM
      • Bilezikian JP
      • Turner SA
      • McCary LC
      • Guo MD
      • Peacock M
      The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism.
      Hereditary disorders, including familial hyperparathyroidism, multiple endocrine neoplasia syndrome (type 1 and 2A), and hyperparathyroidism-jaw tumor syndrome, account for approximately 10% of patients with primary hyperparathyroidism.
      • Kearns AE
      • Thompson GB
      Medical and surgical management of hyperparathyroidism [published correction appears in Mayo Clin Proc. 2002;77:298].
      Primary hyperparathyroidism is associated with hypercalcemia and inappropriately high PTH levels (after adjusting for the level of serum calcium). However, measurement of calciotropic hormones during skeletal evaluation has led to identification of normocalcemic individuals with elevated PTH levels. This condition called incipient or eucalcemic primary hyperparathyroidism may represent the earliest manifestation of primary hyperparathyroidism.
      • Peacock M
      • Bilezikian JP
      • Klassen PS
      • Guo MD
      • Turner SA
      • Shoback D
      Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism.
      Benign familial hypocalciuric hypercalcemia is characterized by hypercalcemia and relative hypocalciuria. This autosomal dominant disorder is distinguished from primary hyperparathyroidism by a calcium clearance-creatinine clearance ratio [(24-hour urinary calcium × serum creatinine level)/(24-hour urinary creatinine level × serum calcium)] cutoff of 0.01. Familial hypocalciuric hypercalcemia is present at birth; thus, a previously documented normal serum calcium level excludes this diagnosis.
      • Kearns AE
      • Thompson GB
      Medical and surgical management of hyperparathyroidism [published correction appears in Mayo Clin Proc. 2002;77:298].

      SURGICAL TREATMENT GUIDELINES

      No medical therapies have been approved by the Food and Drug Administration for the treatment of primary hyperparathyroidism, and parathyroid surgery is the only definitive cure.
      • Kearns AE
      • Thompson GB
      Medical and surgical management of hyperparathyroidism [published correction appears in Mayo Clin Proc. 2002;77:298].
      • Taniegra ED
      Hyperparathyroidism.
      • Bilezikian JP
      • Potts Jr, JT
      • El-Hajj Fuleihan G
      • et al.
      Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century.

      Fuleihan Gel-H. Clinical manifestations of primary hyperparathyroidism. In: Rose BD, ed. UpToDate Waltham, Ma; 2005.

      • Utiger RD
      Treatment of primary hyperparathyroidism.

      Agus ZS. Management of asymptomatic primary hyperparathyroidism. In: Rose BD. ed. UpToDate. Waltham, Ma; 2005.

      A National Institutes of Health consensus panel on primary hyperparathyroidism recently revised parathyroid surgery guidelines for asymptomatic patients (Table 2).
      • Bilezikian JP
      • Potts Jr, JT
      • El-Hajj Fuleihan G
      • et al.
      Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century.
      The panel confirmed the recommendation of parathyroidectomy for any patient with symptomatic hyperparathyroidism involving target organs, such as those with nephrolithiasis, severe bone disease, or neuromusculardysfunction.
      • Bilezikian JP
      • Potts Jr, JT
      • El-Hajj Fuleihan G
      • et al.
      Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century.
      However, many patients with asymptomatic primary hyperparathyroidism do not meet the criteria recommended for surgery. In addition, many patients (symptomatic or asymptomatic) voluntarily defer surgery or have comorbid conditions that preclude surgery.
      • Bilezikian JP
      • Potts Jr, JT
      • El-Hajj Fuleihan G
      • et al.
      Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century.
      • Shoback DM
      • Bilezikian JP
      • Turner SA
      • McCary LC
      • Guo MD
      • Peacock M
      The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism.
      TABLE 2National Institutes of Health Guidelines for Parathyroidectomy in Asymptomatic Patients With Primary Hyperparathyroidism
      • Bilezikian JP
      • Potts Jr, JT
      • El-Hajj Fuleihan G
      • et al.
      Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century.
      • Serum calcium 1.0 mg/dL above the upper limit of normal
      • 24-h urinary calcium >400 mg
      • Creatinine clearance reduced by 30%
      • Bone mineral density T score less than −2.5 SD at any site
      • Age <50 y

      INITIAL EVALUATION

      The initial evaluation of a patient with symptomatic primary hyperparathyroidism includes measuring the serum calcium and PTH levels. These values should be measured simultaneously because of variations that occur with respect to time, blood volume, and dietary intake. Elevated PTH production in the presence of persistent hypercalcemia confirms the diagnosis of primary hyperparathyroidism.
      • Taniegra ED
      Hyperparathyroidism.

      INPATIENT MANAGEMENT

      Symptomatic patients should be hospitalized if they present with severe hyperparathyroidism-induced hypercalcemia, dehydration, or cardiovascular or neurologic complications. Initial treatment with intravenous saline solution gradually replaces lost fluids and increases urinary calcium excretion. However, saline solution rarely amends serum calcium concentrations in patients with moderate to severe hypercalcemia. Once fluid repletion is accomplished, a loop diuretic may be administered to inhibit sodium reabsorption at the ascending limb of the loop of Henle, reduce the passive reabsorption of calcium, and increase urinary calcium excretion.

      Agus ZS, Savarese DMF, Berenson JR. Treatment of hypercalcemia. In: Rose BD. ed. UpToDate. Waltham, Ma; 2005.

      Patients must be closely monitored for complications caused by aggressive diuresis, including hypokalemia, hypomagnesemia, and acute renal insufficiency. Drugs such as intravenous bisphosphonates or subcutaneous calcitonin may be administered to decrease bone resorption during acute hypercalcemia. Although zolendronate has been recommended

      Agus ZS, Savarese DMF, Berenson JR. Treatment of hypercalcemia. In: Rose BD. ed. UpToDate. Waltham, Ma; 2005.

      for lowering serum calcium levels during malignancy-induced hypercalcemia and may be beneficial for patients with primary hyperparathyroidism, it is not approved by the Food and Drug Administration for such use. Etidronate, clodronate, and pamidronate are first-generation bisphosphonates that may be used, but they are relatively weaker inhibitors of bone resorption compared with zolendronate. Calcitonin is also a relatively weak agent. It increases renal calcium excretion and decreases bone resorption by interference with osteoclast maturation, but its efficacy is limited to the first 48 hours, even with repeated doses.

      Agus ZS, Savarese DMF, Berenson JR. Treatment of hypercalcemia. In: Rose BD. ed. UpToDate. Waltham, Ma; 2005.

      After acute complications of primary hyperparathyroidism have been addressed, the possibility of parathyroidectomy should be considered.

      OUTPATIENT MANAGEMENT

      All management strategies outlined in this section pertain to patients with symptomatic hyperparathyroidism who are not surgical candidates because of medical contraindications or who have elected not to undergo parathyroidectomy for the treatment of primary hyperparathyroidism. These strategies may also be applied to patients with asymptomatic primary hyperparathyroidism who decline surgery.

      Monitoring

      Close monitoring is critical during outpatient management. Although no method is available to predict the timing of disease progression in an individual patient, 27% of patients with asymptomatic primary hyperparathyroidism who initially do not meet surgical criteria develop at least 1 surgical indication during 10 years of follow-up.
      • Silverberg SJ
      • Shane E
      • Jacobs TP
      • Siris E
      • Bilezikian JP
      A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery [published correction appears in N Engl J Med. 2000;342:144].
      If surgery is not recommended or is declined, patients should be informed of the signs of worsening disease and the critical need for regular follow-up visits throughout their lifetime. Recommendations for monitoring include measuring serum creatinine levels and bone density (lumbar spine, hip, and forearm) once a year and measuring serum calcium levels twice a year. To establish the patient's baseline health profile, abdominal ultrasonography or radiography should be performed to identify renal stones. Urinary calcium and creatinine clearance should also be measured. If no renal involvement is detected, baseline studies do not need to be repeated.
      • Shoback DM
      • Bilezikian JP
      • Turner SA
      • McCary LC
      • Guo MD
      • Peacock M
      The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism.

      Diet and Lifestyle Modifications

      Patients with primary hyperparathyroidism should not overly restrict their dietary intake of calcium. In fact, a low-calcium diet may increase PTH secretion, leading to further complications of bone disease. In contrast, a calcium-rich diet may exacerbate the hypercalemia.

      Agus ZS. Management of asymptomatic primary hyperparathyroidism. In: Rose BD. ed. UpToDate. Waltham, Ma; 2005.

      Vitamin D deficiency may increase PTH secretion and bone resorption.

      Agus ZS. Management of asymptomatic primary hyperparathyroidism. In: Rose BD. ed. UpToDate. Waltham, Ma; 2005.

      Therefore, patients should maintain a moderate daily elemental calcium intake of 800 to 1000 mg and a vitamin D intake appropriate for their age and sex (400 IU/d for women >50 years, 600 IU/d for women >75 years, and 400 IU/d for men >65 years).
      • Shoback DM
      • Bilezikian JP
      • Turner SA
      • McCary LC
      • Guo MD
      • Peacock M
      The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism.
      • Utiger RD
      Treatment of primary hyperparathyroidism.

      Agus ZS. Management of asymptomatic primary hyperparathyroidism. In: Rose BD. ed. UpToDate. Waltham, Ma; 2005.

      Pharmacotherapy

      Bisphosphonates. Bisphosphonates are analogues of inorganic pyrophosphate that inhibit osteoclast-mediated bone resorption.
      • Chow CC
      • Chan WB
      • Li JK
      • et al.
      Oral alendronate increases bone mineral density in postmenopausal women with primary hyperparathyroidism.
      • Reasner CA
      • Stone MD
      • Hosking DJ
      • Ballah A
      • Mundy GR
      Acute changes in calcium homeostasis during treatment of primary hyperparathyroidism with risedronate.
      Symptomatic primary hyperparathyroidism leading to parathyroidectomy is frequently associated with a decrease in cortical bone density and relative preservation of trabecular bone density,
      • Khan AA
      • Bilezikian JP
      • Kung AW
      • et al.
      Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial.
      and bisphosphonates are a promising group of medications for the treatment of bone loss. This finding is interesting because administration of a bisphosphonate with teriparatide (recombinant human parathyroid hormone) blunts the improvement in bone mineral density attained with teriparatide alone.
      • Black DM
      • Greenspan SL
      • Ensrud KE
      • PaTH Study Investigators
      • et al.
      The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis.
      • Finkelstein JS
      • Hayes A
      • Hunzelman JL
      • Wyland JJ
      • Lee H
      • Neer RM
      The effects of parathyroid hormone, alendronate, or both in men with osteoporosis.
      Alendronate, the most widely studied bisphosphonate, markedly improved bone mineral density at the lumbar spine (6.9% increase) and hip (3.7% increase) in patients with asymptomatic primary hyperparathyroidism after 2 years of therapy.
      • Khan AA
      • Bilezikian JP
      • Kung AW
      • et al.
      Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial.
      However, this study found no change from baseline measurements in serum calcium, PTH, or urine calcium levels. A separate 2-year study of 32 patients with primary hyperparathyroidism also showed clear improvement of bone mineral density at the lumbar spine (4.0% increase) after alendronate treatment but failed to show improvement at the hip or mid radius.
      • Parker CR
      • Blackwell PJ
      • Fairbairn KJ
      • Hosking DJ
      Alendronate in the treatment of primary hyperparathyroid-related osteoporosis: a 2-year study.
      Serum calcium and PTH levels were unchanged from baseline measurements at the end of the study. Chow et al
      • Chow CC
      • Chan WB
      • Li JK
      • et al.
      Oral alendronate increases bone mineral density in postmenopausal women with primary hyperparathyroidism.
      reported similar results, with considerable improvement of bone mineral density at the lumbar spine and femoral neck. They also observed a reduction in serum calcium levels but no change in PTH levels after 1 year. The most commonly reported adverse effect was mild dyspepsia, but it was not severe enough to discontinue therapy.
      • Chow CC
      • Chan WB
      • Li JK
      • et al.
      Oral alendronate increases bone mineral density in postmenopausal women with primary hyperparathyroidism.
      • Khan AA
      • Bilezikian JP
      • Kung AW
      • et al.
      Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial.
      • Parker CR
      • Blackwell PJ
      • Fairbairn KJ
      • Hosking DJ
      Alendronate in the treatment of primary hyperparathyroid-related osteoporosis: a 2-year study.
      Because alendronate improves bone mineral density and appears to have few adverse effects, it should be considered as an alternative nonsurgical treatment for patients with primary hyperparathyroidism-related osteoporosis.
      • Khan AA
      • Bilezikian JP
      • Kung AW
      • et al.
      Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial.
      Risedronate, a potent oral bisphosphonate, reduced fasting serum calcium levels and markers of bone turnover (ie, alkaline phosphatase, N-telopeptide, osteocalcin) in a study of 19 patients with primary hyperparathyroidism.
      • Reasner CA
      • Stone MD
      • Hosking DJ
      • Ballah A
      • Mundy GR
      Acute changes in calcium homeostasis during treatment of primary hyperparathyroidism with risedronate.
      However, serum calcium levels increased after the introduction of an oral calcium load. Additional studies are required to evaluate the efficacy of risedronate before such treatment can be recommended for patients with hyperparathyroidism.
      Calcimimetics. Calcimimetic agents increase the sensitivity of calcium-sensing receptors in parathyroid chief cells. Patients with hyperparathyroidism are not as responsive as healthy people to changes in serum calcium concentrations and often have increased secretion of PTH in response to elevated calcium levels.
      • Shoback DM
      • Bilezikian JP
      • Turner SA
      • McCary LC
      • Guo MD
      • Peacock M
      The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism.
      Cinacalcet directly lowers PTH secretion by enhancing receptor sensitivity.
      • Shoback DM
      • Bilezikian JP
      • Turner SA
      • McCary LC
      • Guo MD
      • Peacock M
      The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism.
      Shoback et al
      • Shoback DM
      • Bilezikian JP
      • Turner SA
      • McCary LC
      • Guo MD
      • Peacock M
      The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism.
      reported reductions in serum calcium and PTH concentrations after oral administration of cinacalcet. Serum calcium levels decreased after 1 day of treatment and remained within the reference range for the rest of the study, and PTH levels decreased by 20%. Patients tolerated the cinacalcet well and reported few adverse events. The most common adverse effect, paresthesia, was noted in 9 of the 22 patients. Peacock et al
      • Peacock M
      • Bilezikian JP
      • Klassen PS
      • Guo MD
      • Turner SA
      • Shoback D
      Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism.
      found similar results in a 52-week randomized, double-blind, placebo-controlled study that investigated the long-term efficacy and safety of cinacalcet for reducing serum calcium and PTH in patients with mild or moderate primary hyperparathyroidism. They reported that 73% of cinacalcet-treated patients and 5% of placebo-treated patients achieved normocalcemia (serum calcium <10.3 mg/dL) with at least a 0.5 mg/dL reduction from baseline. Plasma PTH levels decreased by 7.6% in the cinacalcet group and increased by 7.7% in the placebo group. The most commonly reported adverse effects were nausea (28% in cinacalcet-treated patients and 16% in the placebo group) and headache (cinacalcet, 23%; placebo, 41%). Cinacalcet is a promising nonsurgical alternative therapy, but additional studies are required to assess its ability to improve bone mineral density. Cinacalcet was recently approved by the Food and Drug Administration for the treatment of hypercalcemia in patients with secondary hyperparathyroidism and chronic kidney disease who are undergoing dialysis.
      Raloxifene. Raloxifene is a selective estrogen receptor modulator that reduces bone resorption and overall bone turnover. It is a partial agonist of estrogen receptors α and β in bone and lipid metabolism, and it is a partial antagonist of estrogen receptors α and β in the breast and uterus.
      • Zanchetta JR
      • Bogado CE
      Raloxifene reverses bone loss in postmenopausal women with mild asymptomatic primary hyperparathyroidism.
      Zanchetta and Bogado
      • Zanchetta JR
      • Bogado CE
      Raloxifene reverses bone loss in postmenopausal women with mild asymptomatic primary hyperparathyroidism.
      reported that raloxifene lowered total serum calcium levels by 1 mg/dL after 12 months in postmenopausal women with primary hyperparathyroidism. Specific markers of bone turnover and urinary calcium excretion decreased below baseline values after 12 months. Although PTH concentrations decreased after 6 months, they returned to baseline values after 12 months. A randomized, placebo-controlled, double-blind trial of 18 postmenopausal women with asymptomatic primary hyperparathyroidism yielded similar results after 8 weeks of treatment with raloxifene.
      • Rubin MR
      • Lee KH
      • McMahon DJ
      • Silverberg SJ
      Raloxifene lowers serum calcium and markers of bone turnover in postmenopausal women with primary hyperparathyroidism.
      Four weeks after treatment was discontinued, serum calcium levels and markers of bone turnover returned to baseline values.
      Percutaneous Alcohol Ablation. Ethanol has been used as a sclerosing agent for the treatment of benign and malignant lesions, possibly through a role in direct coagulative necrosis and local partial or complete small-vessel thrombosis.
      • Bennedbaek FN
      • Karstrup S
      • Hegedus L
      Percutaneous ethanol injection therapy in the treatment of thyroid and parathyroid diseases.
      Percutaneous alcohol ablation of the parathyroid gland has been suggested as an alternative treatment for patients with primary hyperparathyroidism who meet surgical criteria but decline or have contraindications to surgery.
      • Harman CR
      • Grant CS
      • Hay ID
      • et al.
      Indications, technique, and efficacy of alcohol injection of enlarged parathyroid glands in patients with primary hyperparathyroidism.
      Harman et al
      • Harman CR
      • Grant CS
      • Hay ID
      • et al.
      Indications, technique, and efficacy of alcohol injection of enlarged parathyroid glands in patients with primary hyperparathyroidism.
      conducted an 11-year study of 36 patients with primary hyperparathyroidism who underwent percutaneous alcohol ablation. During a 16-month postoperative period, 33% of the patients remained eucalcemic, and the rest had adequately controlled serum calcium levels. Two patients experienced recurrent laryngeal nerve injury and 4 had temporary hypocalcemia, but no long-term complications were reported. A separate study of 32 patients undergoing ultrasonographically guided ethanol ablation showed similar results during a 6-month period after surgery.
      • Karstrup S
      • Hegedus L
      • Holm HH
      Ultrasonically guided chemical parathyroidectomy in patients with primary hyperparathyroidism: a follow-up study.
      In patients who undergo this procedure, serum calcium levels should be closely monitored because multiple treatments may be necessary if hypercalcemia recurs.
      • Harman CR
      • Grant CS
      • Hay ID
      • et al.
      Indications, technique, and efficacy of alcohol injection of enlarged parathyroid glands in patients with primary hyperparathyroidism.
      Estrogen Therapy. Postmenopausal women with primary hyperparathyroidism may benefit from estrogen replacement therapy. Although serum PTH levels are not affected, decreased bone resorption, a minor reduction (~0.5 mg/dL) in serum calcium levels, a decline in markers of bone turnover, and improvement in bone mineral density have been reported after estrogen therapy.

      Agus ZS. Management of asymptomatic primary hyperparathyroidism. In: Rose BD. ed. UpToDate. Waltham, Ma; 2005.

      • Parker CR
      • Blackwell PJ
      • Fairbairn KJ
      • Hosking DJ
      Alendronate in the treatment of primary hyperparathyroid-related osteoporosis: a 2-year study.
      • Rubin MR
      • Lee KH
      • McMahon DJ
      • Silverberg SJ
      Raloxifene lowers serum calcium and markers of bone turnover in postmenopausal women with primary hyperparathyroidism.
      However, estrogen therapy should not be the first choice for postmenopausal women with primary hyperparathyroidism because of the associated risks.

      Agus ZS. Management of asymptomatic primary hyperparathyroidism. In: Rose BD. ed. UpToDate. Waltham, Ma; 2005.

      Cessation of estrogen or hormone therapy after menopause may unmask underlying mild primary hyperparathyroidism. Such patients should be evaluated as indicated clinically.
      Medications to Avoid. Patients with primary hyperparathyroidism should avoid several medications such as thiazide diuretics, which enhance resorption of calcium in the distal convoluted tubule.
      • Taniegra ED
      Hyperparathyroidism.
      • Ives HE
      Diuretic agents.
      Lithium carbonate may induce hypercalcemia by altering the PTH secretion curve, and patients taking lithium require higher calcium levels to lower PTH secretion.
      • Potts Jr, JT
      Diseases of the parathyroid gland and other hyper- and hypocalcemic disorders.
      To avoid the risk of volume depletion or nephrolithiasis, patients should be encouraged to drink at least six 8-oz glasses of water per day.
      • Utiger RD
      Treatment of primary hyperparathyroidism.

      Agus ZS. Management of asymptomatic primary hyperparathyroidism. In: Rose BD. ed. UpToDate. Waltham, Ma; 2005.

      Patients with hypercalcemia can easily become volume depleted because of hypercalcemia-induced urinary salt wasting.

      Agus ZS, Savarese DMF, Berenson JR. Treatment of hypercalcemia. In: Rose BD. ed. UpToDate. Waltham, Ma; 2005.

      Participation in regular physical activity minimizes bone resorption and fracture risk.

      Agus ZS. Management of asymptomatic primary hyperparathyroidism. In: Rose BD. ed. UpToDate. Waltham, Ma; 2005.

      SUMMARY

      Patients with primary hyperparathyroidism have hypercalcemia and elevated serum PTH levels. Although surgery is the definitive cure, not all patients undergo parathyroidectomy. Some patients have comorbid conditions that preclude surgical treatment or do not meet surgical criteria for other reasons, and many patients seek alternative therapies. If surgery is not performed, the physician and patient must adhere to the guidelines established for monitoring primary hyperparathyroidism. Patients should understand the importance of diet and exercise and be familiar with symptoms of disease progression. Patients with hyperparathyroidism-induced osteoporosis may be considered for treatment with alendronate or raloxifene. If the benefit outweighs the risk, estrogen replacement is another treatment option. Although no medical treatment has been approved for primary hyperparathyroidism, calcimimetics may reduce serum calcium and PTH levels. Finally, percutaneous alcohol ablation of the parathyroid gland may be a suitable treatment for patients who are unwilling or unable to undergo parathyroidectomy.

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      Linked Article

      • CORRECTION
        Mayo Clinic ProceedingsVol. 82Issue 7
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          Incorrect term: In the article by Farford et al entitled “Nonsurgical Management of Primary Hyperparathyroidism,” published in the March 2007 issue of Mayo Clinic Proceedings (Mayo Clin Proc. 2007;82:351-355), an incorrect term was published in Table 1 on page 352. The third entry under the heading “Cardiovascular” should read as follows: Shortened QT interval.
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