Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Case-based review Diagnosis and Management of Primary Hyperparathyroidism Case Study and Commentary, Natalie E. Cusano, MD, and John P. Bilezikian, MD Abstract • Objective: To review new developments in the diagnosis and management of primary hyperparathyroidism. • Methods: Review of the literature. • Results: Primary hyperparathyroidism is one of the most common endocrine disorders, especially among postmenopausal women. Patients with hypercalcemia can be diagnosed with primary hyperparathyroidism in the setting of elevated or inappropriately normal parathyroid hormone (PTH) levels. A newer presentation of primary hyperparathyroidism has been described, normocalcemic primary hyperparathyroidism, in which patients have normal total and ionized serum calcium concentrations and consistently elevated PTH levels, excluding secondary etiologies of hyperparathyroidism. Most patients with primary hyperparathyroidism present asymptomatically, although decreased bone density at the distal 1/3 radius site is usually noted at the time of diagnosis. • Conclusion: Patients with symptomatic primary hyperparathyroidism and those with asymptomatic disease who meet criteria for surgery should be advised to have surgical removal of the abnormal parathyroid gland(s). Those who do not meet criteria for surgery can be managed nonoperatively with surveillance by biochemical and densitometric measurements. Pharmacologic options are available for those who meet surgical criteria but either refuse surgery or are not deemed suitable for surgery. O ver the past 40 years, the clinical presentation of primary hyperparathyroidism has changed from a disorder with overt symptomatology to one that presents most commonly asymptomatically. It is discovered most often in the context of a biochemical screening test in which the discovery of hypercalcemia is a surprise. Investigation of this more modern phenotype of primary hyperparathyroidism has revealed new insights into the diagnosis, management, and natural history of www.jcomjournal.com primary hyperparathyroidism. This review will cover the new developments in the field. CASE STUDY Initial Presentation A 72-year-old Hispanic woman with a history of hypertension and morbid obesity was referred to an endocrinologist for hypercalcemia noted on routine laboratory evaluation. History Her past medical and surgical history was otherwise significant for hyperlipidemia, hypothyroidism, depression, gastroesophageal reflux disease, and chronic headache. She denied a history of fracture or nephrolithiasis. Review of systems was significant only for chronic constipation. Her medications included amlodipine, telmisartan, ezetimibe-simvastatin, levothyroxine, citalopram, and lansoprazole. The patient was born and raised in the Dominican Republic; social history was otherwise unremarkable. Family history was significant for leukemia and breast cancer but negative for parathyroid disease or other endocrine disorders. Physical Examination, Laboratory, and Radiographic Evaluation Examination was significant for a body mass index of 47.5 kg/m2, absence of thyromegaly or nodules, absence of neck masses, absence of kyphosis or vertebral tenderness. Her most recent laboratory testing prior to evaluation was significant for a serum calcium level of 10.8 mg/dL (reference range [rr], 8.6– 10.2), ionized calcium of 1.53 mM/L (rr, 1.12–1.32), parathyroid hormone (PTH) 104 pg/mL (rr, 10–65), From the Department of Medicine, Division of Endocrinology, College of Physicians and Surgeons, Columbia University, New York, NY. Vol. 20, No. 4 April 2013 JCOM 181 Primary hyperparathyroidism 25-hydroxyvitamin D 28 ng/mL (rr, 30–100), albumin 4.0 g/dL (rr, 3.5–5.5), creatinine 0.8 mg/dL (rr, 0.50– 0.90), phosphorus 2.9 mg/dL (rr, 2.5–4.3), and total alkaline phosphatase 102 U/L (rr, 33–96). A bone mineral density was obtained and demonstrated T-scores of –0.3 at the lumbar spine, –0.3 at the femoral neck, +1.2 at the total hip, and –1.5 at the distal 1/3 radius. 24-hour urine calcium excretion was obtained and was noted to be 240 mg (rr, 50–250). • What is the epidemiology of primary hyperparathyroidism? What are the biochemical and clinical features? Maintenance of sufficient levels of calcium is required for many physiologic processes, among them normal neuromuscular function and bone mineralization. PTH produced by the parathyroid glands is an important regulator of serum calcium through its effects on bone, the kidney, and intestines. In primary hyperparathyroidism, one or more of the parathyroid glands become enlarged and overactive. Primary hyperparathyroidism is, thus, a disorder characterized by elevated levels of PTH and traditionally by hypercalcemia. Primary hyperparathyroidism is one of the most common endocrine disorders, with an estimated prevalence in the United States between 1 and 2 per 1000. Most patients present after the age of 45 years; women are affected more often than men by 3:1. Prior to the advent of the multichannel autoanalyzer in the 1970s, classical primary hyperparathyroidism presented usually as a symptomatic disorder [1–3]. The original description more than 70 years ago as a disease of “bones, stones and groans” was apt. Overt skeletal disease was readily recognized by radiographic features of osteitis fibrosa cystica: “salt and pepper” degranulation of the skull, subperiosteal bone resorption of the distal phalanges, brown tumors, loss of distal clavicular appearance and bone cysts [4]. With serum calcium values now routinely available as a biochemical screening test result, the clinical profile of primary hyperparathyroidism has evolved into a disorder that presents most commonly in an asymptomatic fashion. In these patients, the discovery of hypercalcemia is made incidentally [5]. The typical biochemical features of primary hyperparathyroidism are shown in Table 1 [6,7]. Serum calcium is usually within 1.0 mg/dL (0.25 mmol/L) above 182 JCOM April 2013 Vol. 20, No. 4 the upper limit of normal. Serum phosphorus is usually in the low normal range, although 25% of patients will have levels that are frankly low. The average vitamin D level, as measured by 25-hydroxyvitamin D, is low, averaging 20 ng/mL. Vitamin D deficiency is due in part to the effects of PTH to facilitate the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D [8]. Up to 25% of patients will have frankly elevated 1,25-dihydroxyvitamin D levels. Total alkaline phosphatase activity and more specific markers of bone turnover such as osteocalcin and serum and urine N- and C-telopeptide levels, are all usually in the high normal range. 24-hour urinary calcium excretion is typically in the upper range of normal, with a 40% incidence of frank hypercalciuria [9]. While the incidence of hypercalciuria has not changed over the past 60 years, the incidence of renal stone disease has fallen markedly. This speaks to an interesting point, namely that in primary hyperparathyroidism, hypercalciuria is not a risk factor for kidney stones [7]. Despite the fact that most patients are discovered incidentally, and x-rays rarely show classical findings of primary hyperparathyroidism, bone mass is typically reduced when it is measured by dual energy x-ray absorptiometry (DXA). Primary hyperparathyroidism tends to preferentially affect cortical (also known as compact) bone, the bone that forms the outer shell, or envelope, of bones. The densitometric profile of primary hyperparathyroidism shows reductions at the distal 1/3 forearm, a site composed primarily of cortical bone [5,6]. Highresolution imaging of the radius [10] and histomorphometric analysis of bone biopsies [11] have confirmed this finding. In contrast, the lumbar spine, a site composed primarily of trabecular bone (also known as spongy bone), tends to be preserved [12]. In estrogen-deficient, postmenopausal women without primary hyperparathyroidism, the lumbar spine site is at greatest risk for bone loss, making the observation that trabecular bone is preserved in these individuals even more noteworthy. This observation, namely preservation of trabecular bone in primary hyperparathyroidism, offered clues to the osteoanabolic potential of PTH [13]. The administration of low-dose, intermittent PTH revealed this osteoanabolic property and led to the development of PTH as a treatment for osteoporosis [14–16]. Information about fracture risk in primary hyperparathyroidism is inconsistent due to lack of rigorous prospective data and the inclusion of populations with varying disease severity [17–20]. In a study by Vignali et al [21] stratifying by disease www.jcomjournal.com Case-based review Table 1. Biochemical Indices in 57 Patients with Asymptomatic Primary Hyperparathyroidism Baseline Values* Normal Range Serum calcium, mg/dL 10.5 ± 0.1 8.4–10.2 Serum parathyroid hormone, pg/mL 116 ± 7 10–65 Urinary calcium, mg/dL Index 236 ± 17 < 300 Alkaline phosphatase, U/L 98 ± 6 Serum 25-hydroxyvitamin D, ng/mL 21 ± 1 < 100 > 30† Serum 1,25-dihyroxyvitamin D, pg/mL 57 ± 2 15–60 Reprinted from reference 6. *Values are mean ± SEM. †Many experts consider 25-hydroxyvitamin D levels > 30 ng/mL to indicate sufficiency. severity, both symptomatic and asymptomatic patients with primary hyperparathyroidism had an increased risk of vertebral fracture. However, those asymptomatic individuals who did not meet surgical criteria did not show an increased risk in comparison to a control population. While nephrolithiasis is still the most common complication of primary hyperparathyroidism, the incidence has fallen to 15% to 20%, much lower than estimates of about 60% in the era prior to the autoanalyzer [5,22]. Other renal manifestations of primary hyperparathyroidism include hypercalciuria and nephrocalcinosis. The frequency of nephrocalcinosis is unknown. An unexplained reduction in the creatinine clearance is also believed to be a potential renal manifestation of primary hyperparathyroidism. Walker et al [23] showed that a creatinine clearance < 60 cc/min is associated with worse indices of skeletal disease as determined by bone biopsy in comparison to subjects with primary hyperparathyroidism whose renal function is normal. Nontraditional manifestations of primary hyperparathyroidism, primarily potential effects on the cardiovascular system and neurocognitive function, are areas of active research. In mild primary hyperparathyroidism, subtle evidence for cardiovascular dysfunction, including altered endovascular function [24] and increased vascular stiffness, has been reported [25,26], but the clinical relevance of these findings are not clear. Nonspecific neurocognitive features, such as weakness, easy fatigability, depression, cognitive impairment, anxiety, and sleep disturbance, have been difficult to identify as direct manifestations of primary hyperparathyroidism. Associated improvement in quality of life and psychological functioning following successful parathyroidectomy has www.jcomjournal.com not been a consistent finding among the 4 groups that have studied this problem recently [27–30]. •What are other presentations of primary hyperparathyroidism? Normocalcemic Primary Hyperparathyroidism A newer clinical presentation of primary hyperparathyroidism has been described over the past decade, characterized by normal total and ionized serum calcium concentrations and consistently elevated PTH levels [31–34]. Patients with normocalcemic primary hyperparathyroidism have no obvious causes for secondary elevations of PTH, such as renal disease or vitamin D deficiency. Identification of this new phenotype of primary hyperparathyroidism is consistent with a biphasic time course of the clinical development of primary hyperparathyroidism [33]. During the first phase, PTH levels are elevated but the serum calcium is normal. Until recently, this phase would not be recognized clinically because PTH levels were not drawn in the context of a normal serum calcium concentration. The second phase, when overt hypercalcemia becomes apparent, is the stage of the disease that has characterized most cohorts of primary hyperparathyroidism until recently. The discovery of this putative first phase of primary hyperparathyroidism, when the serum calcium is normal, would appear to be due to the fact that many osteoporosis and metabolic bone disease units now measure PTH routinely in the evaluation of bone loss. Reports of normocalcemic primary hyperparathyroid- Vol. 20, No. 4 April 2013 JCOM 183 Primary hyperparathyroidism Table 2. Genetic Hyperparathyroid Syndromes Syndrome Main Gene Associated Features Parathyroid pathology Therapy Familial hypocalciuric hypercalcemia CASR Hypocalciuria, rare pancreatitis None (normal) No parathyroidectomy Neonatal severe hyperparathyroidism CASR Life-threatening hypercalcemia Early, 4 large glands Urgent total parathyroidectomy Multiple endocrine neoplasia type 1 MEN1 Pituitary and pancreas tumors Multiglandular Subtotal parathyroidectomy based on severity Multiple endocrine neoplasia type 2A RET Pheochromocytoma and medullary thyroid cancer Multiglandular Subtotal parathyroidectomy based on severity HRPT2 Fibromas in the mandible or the maxilla, parathyroid cancer Parathyroid carcinoma (20%) Surgical resection of cancer if it develops Unknown None Multiglandular Parathyroidectomy based on severity Hyperparathyroidism-jaw tumor syndrome Familial isolated hyperparathyroidism Note: All entries represent typical features of a broad spectrum of disease ism have largely come, therefore, from referral centers in which subjects were under evaluation for bone loss. For example, of the 37 individuals who were described with normocalcemic primary hyperparathyroidism at Columbia University Medical Center [35], 57% had osteoporosis by BMD, 11% had documented fragility fractures, and 14% had nephrolithiasis. The observation that subjects with this putative “early” phase of primary hyperparathyroidism have evidence for skeletal involvement, not different from hypercalcemic cohorts, raises the possibility that there is another population of normocalcemic subjects with primary hyperparathyroidism who would not have evidence for skeletal involvement if they were identified from a general population. Studies are in progress to identify the other form of normocalcemic primary hyperparathyroidism [36,37]. Primary Hyperparathyroidism in the Developing World Interestingly, while primary hyperparathyroidism in the developed world has become a disorder of mild, asymptomatic hypercalcemia, the clinical picture of primary hyperparathyroidism in the developing world, in which vitamin D deficiency is more common and biochemical screening tests are not routinely performed, remains a disease with classic signs and symptoms, including osteitis fibrosa cystica as well as other skeletal and renal complications. Primary hyperparathyroidism in the setting of vitamin D deficiency is associated with a more severe phenotype [7], with larger 184 JCOM April 2013 Vol. 20, No. 4 adenomas, higher serum calcium, parathyroid hormone, and alkaline phosphatase levels, lower bone mineral density, and higher fracture rates [38–42]. • What is the etiology of primary hyperthyroidism? In primary hyperparathyroidism, clones of abnormal parathyroid cells alter the “set-point” sensitivity of the parathyroid gland to calcium and increase the mass of parathyroid tissue. PTH is higher for any given extracellular concentration of calcium [43]. A single gland adenoma is the most common cause of primary hyperparathyroidism, accounting for approximately 80% of cases. Multiple adenomas are reported in 2% to 4% of patients, and 4-gland hyperplasia in 10% to 15%. Very rarely, primary hyperparathyroidism can present as a malignant carcinoma, but the incidence is less than 0.5% among the hyperparathyroid population [39,40]. There are no clinical features that distinguish patients with single versus multiglandular disease. However, younger patients (< 40 years), particularly those with a personal or family history of a multiple endocrine neoplasia (MEN) syndrome, are more likely to have multiglandular disease. Occasionally, parathyroid adenomas will be found in unexpected anatomic locations due to embryonal migration patterns of parathyroid tissue. The most common sites for ectopic adenomas are within the thyroid gland, the superior mediastinum, and within the thymus [2]. www.jcomjournal.com Case-based review Although most patients have sporadic disease, hereditary syndromes in which primary hyperparathyroidism is prominent include MEN types 1 and 2A, hyperparathyroidism-jaw tumor syndrome, neonatal severe primary hyperparathyroidism, and familial isolated hyperparathyroidism (Table 2) [3,44,45]. Ionizing radiation to the head and neck has been associated with the development of primary hyperparathyroidism many decades after exposure [46–48]. This usual etiology is dependent, in part, on dose and time from exposure. The absolute risk with therapeutic doses of radiation remains quite low, < 1% at 35 years and only about 5% after 50 years of follow-up [49]. There are case reports and case series suggesting an association with radioactive iodine therapy for the treatment of benign and malignant thyroid conditions [50–52], although a prospective cohort study failed to demonstrate an increased incidence of parathyroid disease after radioactive iodine treatment, with a mean follow-up time of 21 years [53]. • How is the diagnosis made? The 2 principal causes of hypercalcemia are primary hyperparathyroidism and malignancy. In the outpatient setting, primary hyperparathyroidism is much more common. Patients with hypercalcemia due to malignancy usually have clinically established advanced cancer. The clinical setting distinguishing between these 2 most common etiologies of hypercalcemia is supported further by measurement of the PTH level. It is frankly elevated in about 75% to 80% of patients with primary hyperparathyroidism, and inappropriately normal in the remaining subjects. In contrast, PTH is typically undetectable in patients with malignancy-associated hypercalcemia. An undetectable PTH level in a hypercalcemic individual, however, does not indicate a malignancy because most of the other causes of hypercalcemia, a long list indeed, are associated with suppressed levels of PTH [3]. If the PTH is elevated, the disorders that could be mistaken for primary hyperparathyroidism are small in number. They include familial hypocalciuric hypercalcemia [54] and medications, specifically thiazide diuretics [55] and lithium [56]. Very rarely a malignant tumor has been reported to secrete ectopic PTH, as opposed to the more commonly reported PTH-related peptide (PTHrP) [57–59]. www.jcomjournal.com Familial hypocalciuric hypercalcemia (FHH) is a rare, benign disorder caused by loss of function mutations in the calcium sensing receptor (CASR) gene. A diagnosis of FHH can be suspected by a family history of FHH or a 24-hour urine calcium collection showing very low values for calcium excretion on a normal calcium diet. In FHH, the 24-hour urinary calcium is well under 100 mg/day and calcium to creatinine clearance ratio is less than 0.01 mmol/L [60]. If the calcium-to-creatinine clearance ratio is greater than 0.02, FHH becomes very unlikely. CASR gene analysis for a single point mutation identified in FHH can be considered in a patient with a calcium to creatinine clearance ratio < 0.02 [61]. It is important to distinguish FHH from primary hyperparathyroidism because the parathyroid glands are normal in FHH and surgery is never indicated. It is also important to remember that FHH is a rare disorder while primary hyperparathyroidism is a common one. Moreover, since PTH is a calcium-conserving hormone, by facilitating renal tubular calcium reabsorption, a low calcium-tocreatinine clearance ratio does not establish the diagnosis of FHH. Thiazide diuretics can be associated with hypercalcemia due to a number a factors such as thiazide-associated reduced urinary calcium excretion, a metabolic alkalosis resulting in a pH-dependent increase in protein-bound calcium, and increased calcium absorption from the intestines [62,63]. Discontinuation or substitution of the thiazide can be considered if there are no contraindications, with subsequent retesting of calcium and PTH in 3 to 6 months. Most hypercalcemic patients taking thiazide diuretics will ultimately be diagnosed with primary hyperparathyroidism [64]. Lithium decreases sensitivity to calcium within the parathyroid gland and may also reduce urinary calcium excretion [56,65]. Short-term use of lithium might be associated with reversible hypercalcemia but, like thiazide diuretic use, most patients on lithium will have been on lithium for many years when hypercalcemia is discovered [59]. It is not easy to discontinue lithium, as one can often stop or substitute for a thiazide diuretic. The diagnosis of primary hyperparathyroidism in these individuals is usually clear. If they meet criteria for surgery and there are no contraindications to surgery, most experts will proceed to obtain preoperatively localization of the putative parathyroid adenoma. Hypercalcemia, the classical biochemical hallmark of primary hyperparathyroidism, is not always present in traditional primary hyperparathyroidism. Although Vol. 20, No. 4 April 2013 JCOM 185 Primary hyperparathyroidism patients are hypercalcemic most of the time, the serum calcium level can be normal during the course of monitoring. The “normal” serum calcium in these traditionally hypercalcemic individuals is usually in the upper normal range. These individuals do not have “normocalcemic primary hyperparathyroidism” in which the serum calcium is always normal (see above). The diagnostic criteria for normocalcemic primary hyperparathyroidism include consistently normal albumin-adjusted total serum calcium and normal ionized calcium. Additionally, secondary causes of an elevated PTH level must be excluded: • Vitamin D deficiency: There is controversy surrounding the precise threshold value for 25-hydroxyvitamin that leads to an increase in PTH. The Institute of Medicine report [66] concluded that there was insufficient evidence that levels of 25-hydroxyvitamin D ≥ 20 ng/mL are regularly associated with increases in PTH levels in population sampling. However, these studies are confounded by the lack of any prospective data tracking PTH on an individual level as the 25hydroxyvitamin D level is increased. The diagnosis of normocalcemic primary hyperparathyroidism can be made with greater certainty when the 25-hydroxyvitamin D level is greater than 30 ng/mL. In addition, normocalcemic patients with hyperparathyroidism will occasionally become hypercalcemic when 25-hydroxyvitamin D levels are raised to over 30 ng/mL. Ensuring vitamin D sufficiency, therefore, may unmask the latent hypercalcemic state of primary hyperparathyroidism. • Reduced creatinine clearance. Martinez et al [67–69] demonstrated that PTH begins to rise with a glomerular filtration rate < 60 cc/min. • Use of thiazide diuretics and lithium • Hypercalciuria • Gastrointestinal malabsorption • What is the natural history of primary hyperparathyroidism? Natural History Without Surgery Two large, prospective cohorts have helped to define the natural history of the disease and the criteria that are used to determine which patients with asymptomatic primary hyperparathyroidism are candidates for curative surgery. Rao et al [33] followed 80 asymptomatic patients for up to 11 years, during which time there was no worsening 186 JCOM April 2013 Vol. 20, No. 4 of biochemical or densitometric indices. Silverberg et al [5] followed a cohort of 101 asymptomatic patients up to 10 years, showing that while most patients did well, approximately 25% of these patients did progress, with age as the only predictor of disease progression. Patients younger than 50 years of age were approximately 3 times as likely to have disease progression. Rubin et al [6] reported the 15-year follow-up study of these patients, finding that disease progression over that longer time period increased to 37% of the cohort. Particularly noteworthy was accelerated bone loss at the distal 1/3 radius and femoral neck between years 10 and 15. The natural history of normocalcemic primary hyperparathyroidism is less well defined. In the cohort from Columbia University Medical Center [35], 40% developed further signs of primary hyperparathyroidism during a mean follow-up period of 3.1 ± 0.3 years. Hypercalcemia developed in 19% of these individuals. The subjects who became hypercalcemic tended to be older, have higher baseline serum calcium levels, and higher baseline urinary calcium excretion. Natural History With Surgery In the cohort studied by the group at Columbia University Medical Center, 59 patients who underwent successful parathyroid surgery experienced densitometric gains at 5, 10, and 15 years, respectively, of 9%, 6%, and 12% at the lumbar spine; 1%, 7% and 10% at the femoral neck; and 4%, 8%, and 7% at the distal radius. Randomized controlled trials of surgery versus observation [27,28,30] have also shown increased bone density at the hip and/ or lumbar spine. These studies failed to show a change at the distal 1/3 radius site, which is understandable given the short-term follow-up. Using high-resolution peripheral quantitative computed tomography (HRpQCT), subjects 1 year after parathyroidectomy [70] showed increases in cortical and trabecular volumetric bone density in both the radius and tibia along with improvements in bone microarchitecture and estimated strength in the radius. • How is primary hyperparathyroidism managed? Surgical Management Parathyroidectomy is the only curative option for patients with primary hyperparathyroidism. Patients with www.jcomjournal.com Case-based review Table 3. Guidelines for the Treatment of Patients with Asymptomatic Primary Hyperparathyroidism Measurement Surgical Criteria* Medical Surveillance Serum calcium 1.0 mg/dL (0.25 mmol/L) > upper limit of normal Annually Reduced to < 60 cc/min (calculated) T-score < –2.5 at any site‡ and/or Every 1–2 years (3 sites) Creatinine clearance Bone mineral density† Annually previous fragility fracture Age < 50 years N/A Reprinted from reference 80. *Surgery is also indicated in patients for whom medical surveillance is neither desired nor possible. †Consistent with the position established by the International Society for Clinical Densitometry, the use of Z-scores instead of T-scores is recommended in evaluating bone mineral density in premenopausal women and men younger than 50 years. ‡Lumbar spine, total hip, femoral neck or 1/3 radius. symptomatic primary hyperparathyroidism, manifested by kidney stones, fracture or marked hypercalcemia, should be managed surgically with removal of the abnormal parathyroid gland(s). Even with refinements to the surgical procedure over the last decade, it remains exceedingly important that highly experienced surgeons with interest in, and aptitude for, parathyroid surgery perform the procedure [71]. The standard operation for parathyroidectomy used to be a full neck exploration with identification of all 4 parathyroid glands, with the rationale being that 15% to 20% of patients with sporadic primary hyperparathyroidism will have 4-gland hyperplasia. Recent advances in preoperative imaging modalities and in intraoperative monitoring of PTH levels have led to the minimally invasive parathyroidectomy, which can be performed under local anesthesia [72,73]. The minimally invasive operation consists of identification and removal of the abnormal tissue without visualization of the other glands by the surgeon. Before and after the adenoma is removed, an intraoperative PTH level is obtained to confirm that the resected gland was the only source of excess PTH [74]. The abnormal tissue removed is considered to be the entirety of abnormal parathyroid tissue if the intraoperative PTH level falls by greater than 50% to a level into the normal range within 10 minutes after removal of the adenoma. If these criteria are not met, the operation is extended to an exploration of other sites where abnormal parathyroid tissue may be found. Success rates for parathyroid surgery with the minimally invasive procedure are over 90%, similar to the rates obtained with the classical 4-gland exploration [72]. The advantages of the minimally invasive procedure include www.jcomjournal.com its shorter length of time and much more rapid recovery in comparison to general anesthesia. In many centers, the operation is performed on an ambulatory basis without need for overnight observation. In the case of parathyroid hyperplasia, options include subtotal parathyroidectomy (removal of 3.5 glands) or total parathyroidectomy with immediate autotransplantation of parathyroid tissue into the forearm. Should hyperparathyroidism recur, the forearm site provides easy access to the transplanted tissue. Cryopreservation facilities are necessary for autotransplantation in case the initial graft does not take. This approach is often used in cases of familial hyperparathyroidism in which 4-gland disease is most common [75,76]. Preoperative localization studies are necessary in preparation for any parathyroid surgery. The most common localization studies include neck ultrasound, computed tomography (CT) and radionuclide imaging (ie, sestamibi). The sensitivity and specificity of each modality vary among institutions. Ultrasound has the advantages of low cost and ability to identify co-existing thyroid pathology. The sensitivity ranges from 42% to 82% depending on the operator, although the specificity is approximately 90% [77]. Sestamibi can be useful in the identification of ectopic parathyroid tissue and has a sensitivity approaching 90% for single adenomas, with decreased sensitivity for multiple lesions [78]. If the patient is not taking thyroid hormone, double-labeling with 123I and 99T sestamibi is preferred because the thyroid image generated by the 123I can be compute-subtracted from the image obtained by 99T sestamibi. Fourdimensional CT has also proven to be very successful in Vol. 20, No. 4 April 2013 JCOM 187 Primary hyperparathyroidism identifying abnormal parathyroid tissue. Other localization approaches include magnetic resonance imaging and positron emission tomography. Arteriography and selective venous sampling may be needed in patients with persistent or recurrent disease in whom the noninvasive studies were unable to localize the lesion [79]. The Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism in 2008 [80] defined guidelines for the management of asymptomatic primary hyperparathyroidism (Table 3). Surgical management in asymptomatic patients should be considered in those with end-organ effects (osteoporosis at any site, creatinine clearance < 60 cc/min) or a higher likelihood of disease progression (age < 50 years, serum calcium > 1.0 mg/dL above the upper limit of normal). Marked hypercalciuria, a surgical indication in previous consensus conferences, was removed from the most current guidelines because urinary calcium has not been shown in primary hyperparathyroidism to be a risk factor for kidney stones [7]. Medical Management Patients who do not meet surgical criteria can be observed with annual serum calcium, calculated creatinine clearance, and either annual or biannual bone densitometry (Table 3) [80]. Patients should be referred for parathyroid resection if they develop an indication for surgery during the follow-up period. While not part of guidelines, renal imaging with abdominal x-ray, ultrasonography, or CT can be considered in order to rule out renal involvement in subjects with no known history of kidney stones. Whether this approach to detecting renal calcifications should be part of conservative monitoring is a matter of clinical judgment. Patients found to have or to develop renal calcifications (nephrolithiasis or nephrocalcinosis) would become surgical candidates. Patients with primary hyperparathyroidism and vitamin D deficiency present a particularly challenging dilemma due to the potential risk of worsening hypercalcemia with vitamin D supplementation. Moreover, patients with vitamin D deficiency may be at greater risk for developing hypocalcemia due to “hungry bone” syndrome following parathyroidectomy. A few published studies have focused upon the use of relatively high doses of vitamin D [81–84]. These studies show that vitamin D supplementation in primary hyperparathyroidism seems to be well tolerated and does not lead, in general, to worsening hypercalcemia or hypercalciuria. 188 JCOM April 2013 Vol. 20, No. 4 The reports, however, also demonstrate the importance of careful monitoring. The optimal management of vitamin D deficiency is unknown, although most experts would recommend supplementation of 400 to 1000 IU daily and close monitoring of serum and urine calcium. More aggressive repletion of vitamin D deficiency can be considered post-parathyroidectomy to prevent “hungry bone” syndrome. Clinical trials are ongoing to determine optimal management of vitamin D deficiency in primary hyperparathyroidism (NCT00674154, NCT01306656, NCT01329666). Patients who are not surgical candidates, refuse parathyroidectomy, or those with refractory primary hyperparathyroidism following surgery can be considered for medical therapy. Cinacalcet, a calcimimetic, is the only approved medical therapy for primary hyperparathyroidism in the United States, indicated for the treatment of severe hypercalcemia. Cinacalcet is an allosteric modulator of the calcium-sensing receptor that increases its sensitivity to extracellular calcium ions [85]. In a double-blind, randomized, 52-week placebo-controlled trial of 78 patients [86], cinacalcet was shown to significantly lower or normalize serum calcium and PTH levels in subjects with primary hyperparathyroidism. Serum phosphate was increased. Bone mineral density was unchanged. Cinacalcet was well tolerated, with the most common adverse effects being nausea and headache. The open-label 4.5-year extension of this trial [87] continued to show efficacy of cinacalcet. In primary hyperparathyroidism, most patients can be well controlled on a daily dose of 30 mg, although the official recommendation is to start with a twice daily dosing regimen. It is very uncommon for patients with primary hyperparathyroidism to require more than a twice daily dosing regimen. Conversely, in parathyroid cancer, much larger doses may be required, up to a maximum of 90 mg 4 times daily. Such high doses are poorly tolerated. Antiresorptive therapeutic approaches have also been used in patients with primary hyperparathyroidism. In small studies, hormone replacement therapy [88–92], raloxifene [93,94], and bisphosphonates, with alendronate being the most studied [95–98], have all been shown to reduce bone turnover. Estrogen and raloxifene reduce the serum calcium concentration. Alendronate increases bone mineral density. However, there are no data on fracture efficacy with any of these therapies. An ongoing trial is investigating use of denosumab, a monoclonal antibody against receptor activator of www.jcomjournal.com Case-based review nuclear factor kappa B ligand (RANKL), in postmenopausal women with primary hyperparathyroidism (NCT01558115). • What are considerations for the approach to normocalcemic primary hyperparathyroidism? At the time of the National Institutes of Health Consensus Conference in 2008, the expert panel concluded that the guidelines for the hypercalcemic form of primary hyperparathyroidism could not be applied to normocalcemic primary hyperparathyroidism since so little was known about this variant. Our approach is to monitor patients with normocalcemic primary hyperparathyroidism similarly to the way we monitor patients with asymptomatic hypercalcemic primary hyperparathyroidism, with annual serum calcium, PTH, and bone mineral density. If the disease evolves into the hypercalcemic form, the guidelines from the Third International Workshop can then be followed [80]. Progression of the disease in other respects, such as worsening bone density, a fracture, or a kidney stone, would signal a more proactive surgical approach to the disease, even if patients continue to remain normocalcemic. Case Follow-up The patient was monitored for 5 years with stable annual serum calcium and PTH values and biannual bone mineral density evaluation. Serum calcium subsequently began to rise and was measured consistently in the 11.2–11.6 mg/dL range. Due to the rise in serum calcium to greater than 1 mg/dL above the normal range, parathyroidectomy was discussed with the patient. Parathyroid sestamibi demonstrated increased radiotracer uptake in the region of the inferior pole of the right thyroid gland, most consistent with a parathyroid adenoma. The patient was referred to an endocrine surgeon for minimally invasive parathyroidectomy. A 0.47-g right lower parathyroid was removed, with intraoperative PTH declining from 244 to 25 pg/mL within 10 minutes. Pathology was consistent with a parathyroid adenoma. She has now been followed 1 year postoperatively with normal serum calcium and PTH values. Conclusion Prior to the advent of the multichannel autoanalyzer in the 1970s, classical primary hyperparathyroidism comwww.jcomjournal.com monly presented with marked hypercalcemia and symptomatic bone or stone disease. This presentation shifted 40 years ago to a disorder characterized by mild hypercalcemia without classical symptomatic features. We appear to have entered a third era in the history of this disease in which patients are now being discovered with normocalcemic primary hyperparathyroidism, defined by normal total and ionized serum calcium concentrations but with PTH levels that are consistently elevated. Our knowledge of normocalcemic primary hyperparathyroidism remains incomplete and further studies are required to further define the disorder. Patients with symptomatic disease or those who meet surgical criteria should be managed with parathyroid resection. Patients with asymptomatic primary hyperparathyroidism who do not meet criteria for surgery can be managed with annual surveillance of biochemical and densitometric indices. Corresponding author: Natalie E. Cusano, MD, Columbia University College of Physicians and Surgeons, Division of Medicine, 630 West 168th St., PH 8W-864, New York, NY 10032, [email protected]. Funding/support: This work was supported in part by National Institutes of Health grants DK32333 and DK095944. Financial disclosures: Dr. Bilezikian is a consultant for Eli Lilly, NPS Pharmaceuticals, Merck, Warner-Chilcott, GSK, and Amgen, and receives research support from NPS Pharmaceuticals and Amgen. References 1. Bilezikian JP, Silverberg SJ. Primary hyperparathyroidism. In: Rosen C, editor. Primer on metabolic bone diseases and disorders of mineral metabolism. 7th ed. Washington, DC:American Society for Bone and Mineral Research; 2009. 2. Bilezikian JP, Marcus R, Levine MA. The parathyroids: basic and clinical concepts. 2nd ed. San Diego: Academic Press; 2001. 3. Bilezikian JP. Primary hyperparathyroidism. Endotextorg. 4. Cope O. The study of hyperparathyroidism at the Massachusetts General Hospital. N Engl J Med 1966;274:1174–82. 5. Silverberg SJ, Shane E, Jacobs TP, et al. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999;341:1249–55. 6. Rubin MR, Bilezikian JP, McMahon DJ, et al. The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years. J Clin Endocrinol Metab 2008;93:3462–70. 7. Silverberg SJ, Lewiecki EM, Mosekilde L, et al. Presentation of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab 2009;94:351–65. Vol. 20, No. 4 April 2013 JCOM 189 Primary hyperparathyroidism 8. Fraser DR, Kodicek E. Regulation of 25-hydroxycholecalciferol-1-hydroxylase activity in kidney by parathyroid hormone. Nature: New biology 1973;241:163–6. 9. Silverberg SJ, Bilezikian JP. Primary hyperparathyroidism. In: DeGroot LJ, Jameson JL, Potts JT, editors. Endocrinology. 6th ed. Philadelphia: Saunders-Elsevier; 2010: 1176–97. 10. Hansen S, Beck Jensen JE, Rasmussen L, et al. Effects on bone geometry, density, and microarchitecture in the distal radius but not the tibia in women with primary hyperparathyroidism: A case-control study using HR-pQCT. J Bone Miner Res 2010;25:1941–7. 11. Christiansen P, Steiniche T, Brockstedt H, et al. Primary hyperparathyroidism: iliac crest cortical thickness, structure, and remodeling evaluated by histomorphometric methods. Bone 1993;14:755–62. 12. Silverberg SJ, Shane E, de la Cruz L, et al. Skeletal disease in primary hyperparathyroidism. J Bone Miner Res 1989;4:283–91. 13. Dempster DW, Muller R, Zhou H, et al. Preserved threedimensional cancellous bone structure in mild primary hyperparathyroidism. Bone 2007;41:19–24. 14. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434–41. 15. Rosen CJ, Bilezikian JP. Clinical review 123: Anabolic therapy for osteoporosis. J Clin Endocrinol Metab 2001;86:957–64. 16. Rubin MR, Cosman F, Lindsay R, Bilezikian JP. The anabolic effects of parathyroid hormone. Osteoporosis Int 2002;13:267–77. 17. Khosla S, Melton LJ 3rd, Wermers RA, et al. Primary hyperparathyroidism and the risk of fracture: a populationbased study. J Bone Miner Res 1999;14:1700–7. 18. Wilson RJ, Rao S, Ellis B, et al. Mild asymptomatic primary hyperparathyroidism is not a risk factor for vertebral fractures. Ann Intern Med 1988;109:959–62. 19. Melton LJ 3rd, Atkinson EJ, O’Fallon WM, Heath H 3rd. Risk of age-related fractures in patients with primary hyperparathyroidism. Arch Intern Med 1992;152:2269–73. 20. Mosekilde L. Primary hyperparathyroidism and the skeleton. Clin Endocrinol 2008;69:1–19. 21. Vignali E, Viccica G, Diacinti D, et al. Morphometric vertebral fractures in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab 2009;94:2306–12. 22. Rejnmark L, Vestergaard P, Mosekilde L. Nephrolithiasis and renal calcifications in primary hyperparathyroidism. J Clin Endocrinol Metab 2011;96:2377–85. 23. Walker MD, Dempster DW, McMahon DJ, et al. Effect of renal function on skeletal health in primary hyperparathyroidism. J Clin Endocrinol Metab 2012;97:1501–7. 24. Carrelli A, Walker M, DiTullio MR, et al. Endothelial function in mild primary hyperparathyroidism. Clin Endocrinol 2013;78:204–9. 25. Rubin MR, Maurer MS, McMahon DJ, et al. Arterial stiff- 190 JCOM April 2013 Vol. 20, No. 4 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. ness in mild primary hyperparathyroidism. J Clin Endocrinol Metab 2005;90:3326–30. Smith JC, Page MD, John R, et al. Augmentation of central arterial pressure in mild primary hyperparathyroidism. J Clin Endocrinol Metab 2000;85:3515–9. Rao DS, Phillips ER, Divine GW, Talpos GB. Randomized controlled clinical trial of surgery versus no surgery in patients with mild asymptomatic primary hyperparathyroidism. J Clin Endocrinol Metab 2004;89:5415–22. Ambrogini E, Cetani F, Cianferotti L, et al. Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J Clin Endocrinol Metab 2007;92:3114–21. Walker MD, McMahon DJ, Inabnet WB, et al. Neuropsychological features in primary hyperparathyroidism: a prospective study. J Clin Endocrinol Metab 2009;94:1951–8. Bollerslev J, Jansson S, Mollerup CL, et al. Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial. J Clin Endocrinol Metab 2007;92:1687–92. Maruani G, Hertig A, Paillard M, Houillier P. Normocalcemic primary hyperparathyroidism: evidence for a generalized target-tissue resistance to parathyroid hormone. J Clin Endocrinol Metab 2003;88:4641–8. Silverberg SJ, Bilezikian JP. “Incipient” primary hyperparathyroidism: a “forme fruste” of an old disease. J Clin Endocrinol Metab 2003;88:5348–52. Rao DS, Wilson RJ, Kleerekoper M, Parfitt AM. Lack of biochemical progression or continuation of accelerated bone loss in mild asymptomatic primary hyperparathyroidism: evidence for biphasic disease course. J Clin Endocrinol Metab 1988;67:1294–8. Bilezikian JP, Silverberg SJ. Normocalcemic primary hyperparathyroidism. Arq Bras Endocrinol Metabol 2010;54:106–9. Lowe H, McMahon DJ, Rubin MR, et al. Normocalcemic primary hyperparathyroidism: further characterization of a new clinical phenotype. J Clin Endocrinol Metab 2007;92:3001–5. Cusano NE, Wang PY, Cremers SC, et al. Asymptomatic normocalcemic primary hyperparathyroidism: characterization of a new phenotype. Program of the 33rd annual meeting of the American Society of Bone and Mineral Research. San Diego, CA: Abstract SU0167; 2011. Cusano NE, Maalouf NM, Dworakowski E, et al. Epidemiology and natural history of normocalcemic primary hyperparathyroidism and normocalcemic hypoparathyroidism. Program of the 34th annual meeting of the American Society of Bone and Mineral Research. Minneapolis, MN: Abstract MO0134; 2012. Rao DS, Honasoge M, Divine GW, et al. Effect of vitamin D nutrition on parathyroid adenoma weight: pathogenetic and clinical implications. J Clin Endocrinol Metab 2000;85:1054–8. Moosgaard B, Christensen SE, Vestergaard P, et al. Vitamin D metabolites and skeletal consequences in primary hyperparathyroidism. Clin Endocrinol 2008;68:707–15. www.jcomjournal.com Case-based review 40. Inoue Y, Kaji H, Hisa I, et al. Vitamin D status affects osteopenia in postmenopausal patients with primary hyperparathyroidism. Endocrine J 2008;55:57–65. 41. Nordenstrom E, Westerdahl J, Lindergard B, et al. Multifactorial risk profile for bone fractures in primary hyperparathyroidism. World J Surgery 2002;26:1463–7. 42. Rao DS, Agarwal G, Talpos GB, et al. Role of vitamin D and calcium nutrition in disease expression and parathyroid tumor growth in primary hyperparathyroidism: a global perspective. J Bone Miner Res 2002;17 Suppl 2:N75–80. 43. Brown EM. Four-parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue. J Clin Endocrinol Metab 1983;56:572–81. 44. Marx SJ. Hyperparathyroid genes: sequences reveal answers and questions. Endocrine Pract 2011;17 Suppl 3:18–27. 45. Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 2012. 46. Beard CM, Heath H 3rd, O’Fallon WM, et al. Therapeutic radiation and hyperparathyroidism. A case-control study in Rochester, Minn. Arch Intern Med 1989;149:1887–90. 47. Tisell LE, Carlsson S, Fjalling M, et al. Hyperparathyroidism subsequent to neck irradiation. Risk factors. Cancer 1985;56:1529–33. 48. Boehm BO, Rosinger S, Belyi D, Dietrich JW. The parathyroid as a target for radiation damage. N Engl J Med 2011;365:676–8. 49. Schneider AB, Gierlowski TC, Shore-Freedman E, et al. Dose-response relationships for radiation-induced hyperparathyroidism. J Clin Endocrinol Metab 1995;80:254–7. 50. Bondeson AG, Bondeson L, Thompson NW. Hyperparathyroidism after treatment with radioactive iodine: not only a coincidence? Surgery 1989;106:1025–7. 51. Acar T, Gomceli I, Aydin R. Primary hyperparathyroidism due to giant adenoma after treatment with radioactive iodine. N Z Med J 2003;116:U441. 52. Colaco SM, Si M, Reiff E, Clark OH. Hyperparathyroidism after radioactive iodine therapy. Am J Surgery 2007;194:323–7. 53. Fjalling M, Dackenberg A, Hedman I, Tisell LE. An evaluation of the risk of developing hyperparathyroidism after 131I treatment for thyrotoxicosis. Act Chir Scandinav 1983;149:681–6. 54. Fuleihan Gel H. Familial benign hypocalciuric hypercalcemia. J Bone Miner Res 2002;17 Suppl 2:N51–6. 55. Paloyan E, Farland M, Pickleman JR. Hyperparathyroidism coexisting with hypertension and prolonged thiazide administration. JAMA 1969;210:1243–5. 56. Mallette LE, Khouri K, Zengotita H, et al. Lithium treatment increases intact and midregion parathyroid hormone and parathyroid volume. J Clin Endocrinol Metab 1989;68:654–60. 57. Yoshimoto K, Yamasaki R, Sakai H, et al. Ectopic production of parathyroid hormone by small cell lung cancer in a patient with hypercalcemia. J Clin Endocrinol Metab 1989;68:976–81. www.jcomjournal.com 58. Iguchi H, Miyagi C, Tomita K, et al. Hypercalcemia caused by ectopic production of parathyroid hormone in a patient with papillary adenocarcinoma of the thyroid gland. J Clin Endocrinol Metab 1998;83:2653–7. 59. Kandil E, Noureldine S, Khalek MA, et al. Ectopic secretion of parathyroid hormone in a neuroendocrine tumor: a case report and review of the literature. Int J Clin Exp Med 2011;4:234–40. 60. El-Hajj Fuleihan G, Health HI. Familial benign hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. In: Bilezikian JP, Marcus R, Levine MA, editors. The parathyroids: basic and clinical concepts. San Diego: Academic Press; 2001: 607. 61. Christensen SE, Nissen PH, Vestergaard P, et al. Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods. Clin Endocrinol 2008;69:713–20. 62. Middler S, Pak CY, Murad F, Bartter FC. Thiazide diuretics and calcium metabolism. Metabolism: clinical and experimental 1973;22:139–46. 63. Bazzini C, Vezzoli V, Sironi C, et al. Thiazide-sensitive NaCl-cotransporter in the intestine: possible role of hydrochlorothiazide in the intestinal Ca2+ uptake. J Biol Chem 2005;280:19902–10. 64. Wermers RA, Kearns AE, Jenkins GD, Melton LJ 3rd. Incidence and clinical spectrum of thiazide-associated hypercalcemia. Am J Med 2007;120:911 e9–15. 65. Mallette LE, Eichhorn E. Effects of lithium carbonate on human calcium metabolism. Arch Intern Med 1986;146:770–6. 66. Ross AC, Taylor CL, Yaktine AL, Del Valle HB. Dietary reference intakes for calcium and vitamin d. dietary reference intakes. Washington, DC: The National Academies Press; 2011. 67. Martinez I, Saracho R, Montenegro J, Llach F. The importance of dietary calcium and phosphorous in the secondary hyperparathyroidism of patients with early renal failure. Am J Kidney Dis 1997;29:496–502. 68. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003;42:S1–201. 69. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney diseasemineral and bone disorder (CKD-MBD). Kidney Intl Suppl 2009:S1–130. 70. Hansen S, Hauge EM, Rasmussen L, et al. Parathyroidectomy improves bone geometry and microarchitecture in female patients with primary hyperparathyroidism: a oneyear prospective controlled study using high-resolution peripheral quantitative computed tomography. J Bone Miner Res 2012;27:1150–8. 71. Udelsman R, Pasieka JL, Sturgeon C, et al. Surgery for asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab 2009;94:366–72. 72. Udelsman R, Lin Z, Donovan P. The superiority of mini- Vol. 20, No. 4 April 2013 JCOM 191 Primary hyperparathyroidism 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. mally invasive parathyroidectomy based on 1650 consecutive patients with primary hyperparathyroidism. Ann Surgery 2011;253:585–91. Kunstman JW, Udelsman R. Superiority of minimally invasive parathyroidectomy. Adv Surgery 2012;46:171–89. Chen H, Pruhs Z, Starling JR, Mack E. Intraoperative parathyroid hormone testing improves cure rates in patients undergoing minimally invasive parathyroidectomy. Surgery 2005;138:583–97. Wells SA Jr, Farndon JR, Dale JK, et al. Long-term evaluation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy and heterotopic autotransplantation. Ann Surgery 1980;192:451–8. Cohen MS, Dilley WG, Wells SA Jr, et al. Long-term functionality of cryopreserved parathyroid autografts: a 13-year prospective analysis. Surgery 2005;138:1033–40. Van Husen R, Kim LT. Accuracy of surgeon-performed ultrasound in parathyroid localization. World J Surgery 2004;28:1122–6. Civelek AC, Ozalp E, Donovan P, Udelsman R. Prospective evaluation of delayed technetium-99m sestamibi SPECT scintigraphy for preoperative localization of primary hyperparathyroidism. Surgery 2002;131:149–57. Udelsman R, Donovan PI. Remedial parathyroid surgery: changing trends in 130 consecutive cases. Ann Surgery 2006;244:471–9. Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Third International Workshop. J Clin Endocrinol Metab 2009;94:335–9. Grey A, Lucas J, Horne A, et al. Vitamin D repletion in patients with primary hyperparathyroidism and coexistent vitamin D insufficiency. J Clin Endocrinol Metab 2005;90:2122–6. Tucci JR. Vitamin D therapy in patients with primary hyperparathyroidism and hypovitaminosis D. Eur J Endocrinol 2009;161:189–93. Grubbs EG, Rafeeq S, Jimenez C, et al. Preoperative vitamin D replacement therapy in primary hyperparathyroidism: safe and beneficial? Surgery 2008;144:852-8. Isidro ML, Ruano B. Biochemical effects of calcifediol supplementation in mild, asymptomatic, hyperparathyroidism with concomitant vitamin D deficiency. Endocrine 2009;36:305–10. Nemeth EF, Steffey ME, Hammerland LG, et al. Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proceedings of the National Academy of Sciences of the United States of America 1998;95:4040–5. Peacock M, Bilezikian JP, Klassen PS, et al. Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2005;90:135–41. 87. Peacock M, Bolognese MA, Borofsky M, et al. Cinacalcet treatment of primary hyperparathyroidism: biochemical and bone densitometric outcomes in a five-year study. J Clin Endocrinol Metab 2009;94:4860–7. 88. Marcus R, Madvig P, Crim M, et al. Conjugated estrogens in the treatment of postmenopausal women with hyperparathyroidism. Ann Intern Med 1984;100:633–40. 89. Selby PL, Peacock M. Ethinyl estradiol and norethindrone in the treatment of primary hyperparathyroidism in postmenopausal women. N Engl J Med 1986;314:1481–5. 90. Grey AB, Stapleton JP, Evans MC, et al. Effect of hormone replacement therapy on bone mineral density in postmenopausal women with mild primary hyperparathyroidism. A randomized, controlled trial. Ann Intern Med 1996;125:360–8. 91. Diamond T, Ng AT, Levy S, et al. Estrogen replacement may be an alternative to parathyroid surgery for the treatment of osteoporosis in elderly postmenopausal women presenting with primary hyperparathyroidism: a preliminary report. Osteopor Intl 1996;6:329–33. 92. Guo CY, Thomas WE, al-Dehaimi AW, et al. Longitudinal changes in bone mineral density and bone turnover in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab 1996;81:3487–91. 93. Zanchetta JR, Bogado CE. Raloxifene reverses bone loss in postmenopausal women with mild asymptomatic primary hyperparathyroidism. J Bone Miner Res 2001;16:189–90. 94. Rubin MR, Lee KH, McMahon DJ, Silverberg SJ. Raloxifene lowers serum calcium and markers of bone turnover in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab 2003;88:1174–8. 95. Khan AA, Bilezikian JP, Kung AW, et al. Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial. J Clin Endocrinol Metab 2004;89:3319–25. 96. Rossini M, Gatti D, Isaia G, et al. Effects of oral alendronate in elderly patients with osteoporosis and mild primary hyperparathyroidism. J Bone Miner Res 2001;16:113–9. 97. Chow CC, Chan WB, Li JK, et al. Oral alendronate increases bone mineral density in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab 2003;88:581–7. 98. Parker CR, Blackwell PJ, Fairbairn KJ, Hosking DJ. Alendronate in the treatment of primary hyperparathyroid-related osteoporosis: a 2-year study. J Clin Endocrinol Metab 2002;87:4482–9. 99. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:1911–30. Copyright 2013 by Turner White Communications Inc., Wayne, PA. All rights reserved. 192 JCOM April 2013 Vol. 20, No. 4 www.jcomjournal.com