Shonni J. Silverberg

A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery

BACKGROUND AND METHODS In the United States, most patients with primary hyperparathyroidism have few or no symptoms. The need for parathyroidectomy to treat all patients with this disorder has therefore been questioned. We studied the clinical course and development of complications for periods of up to 10 years in 121 patients with primary hyperparathyroidism, 101 (83 percent) of whom were asymptomatic. There were 30 men and 91 women (age range, 20 to 79 years). During the study, 61 patients (50 percent) underwent parathyroidectomy, and 60 patients were followed without surgery. RESULTS Parathyroidectomy in patients with or without symptoms led to normalization of serum calcium concentrations and a mean (+/-SE) increase in lumbar-spine bone mineral density of 8+/-2 percent after 1 year (P=0.005) and 12+/-3 percent after 10 years (P=0.03). Bone mineral density of the femoral neck increased 6+/-1 percent after 1 year (P=0.002) and 14+/-4 percent after 10 years (P=0.002). Bone mineral density of the radius did not change significantly. The 52 asymptomatic patients who did not undergo surgery had no change in serum calcium concentration, urinary calcium excretion, or bone mineral density. However, 14 of these 52 patients (27 percent) had progression of disease, defined as the development of at least one new indication for parathyroidectomy. All 20 patients with symptoms had kidney stones. None of the 12 who underwent parathyroidectomy had recurrent kidney stones, whereas 6 of the 8 patients who did not undergo surgery did have a recurrence. CONCLUSIONS In patients with primary hyperparathyroidism, parathyroidectomy results in the normalization of biochemical values and increased bone mineral density. Most asymptomatic patients who did not undergo surgery did not have progression of disease, but approximately one quarter of them did have some progression.

Diagnosis of Asymptomatic Primary Hyperparathyroidism: Proceedings of the Third International Workshop

BACKGROUND At the Third International Workshop on Asymptomatic Primary Hyperparathyroidism (PHPT) in May 2008, recent data on the disease were reviewed. We present the results of a literature review on issues arising from the clinical presentation and natural history of PHPT. METHODS Questions were developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies was reviewed, and the questions of the International Task Force were addressed by the Consensus Panel. CONCLUSIONS 1) Data on the extent and nature of cardiovascular involvement in those with mild disease are too limited to provide a complete picture. 2) Patients with mild PHPT have neuropsychological complaints. Although some symptoms may improve with surgery, available data remain inconsistent on their precise nature and reversibility. 3) Surgery leads to long-term gains in spine, hip, and radius bone mineral density (BMD). Because some patients have early disease progression and others lose BMD after 8-10 yr, regular monitoring (serum calcium and three-site BMD) is essential in those followed without surgery. Patients may present with normocalcemic PHPT (normal serum calcium with elevated PTH concentrations; no secondary cause for hyperparathyroidism). Data on the incidence and natural history of this phenotype are limited. 4) In the absence of kidney stones, data do not support the use of marked hypercalciuria (>10 mmol/d or 400 mg/d) as an indication for surgery for patients. 5) Patients with bone density T-score -2.5 or less at the lumbar spine, hip, or distal one third radius should have surgery.

The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years.

CONTEXT Primary hyperparathyroidism (PHPT) often presents without classical symptoms such as overt skeletal disease or nephrolithiasis. We previously reported that calciotropic indices and bone mineral density (BMD) are stable in untreated patients for up to a decade, whereas after parathyroidectomy, normalization of biochemistries and increases in BMD ensue. OBJECTIVE The objective of the study was to provide additional insights in patients with and without surgery for up to 15 yr. DESIGN The study had an observational design. SETTING The setting was a referral center. PATIENTS Patients included 116 patients (25 men, 91 women); 99 (85%) were asymptomatic. INTERVENTION Fifty-nine patients (51%) underwent parathyroidectomy and 57 patients were followed up without surgery. MAIN OUTCOME MEASURE BMD was measured. RESULTS Lumbar spine BMD remained stable for 15 yr. However, BMD started to fall at cortical sites even before 10 yr, ultimately decreasing by 10 +/- 3% (mean +/- sem; P < 0.05) at the femoral neck, and 35 +/- 5%; P < 0.05 at the distal radius, in the few patients observed for 15 yr. Thirty-seven percent of asymptomatic patients showed disease progression (one or more new guidelines for surgery) at any time point over the 15 yr. Meeting surgical criteria at baseline did not predict who would have progressive disease. BMD increases in patients who underwent surgery were sustained for the entire 15 yr. CONCLUSIONS Parathyroidectomy led to normalization of biochemical indices and sustained increases in BMD. Without surgery, PHPT progressed in one third of individuals over 15 yr; meeting surgical criteria at the outset did not predict this progression. Cortical bone density decreased in the majority of subjects with additional observation time points and long-term follow-up. These results raise questions regarding how long patients with PHPT should be followed up without intervention.

Bone mass, vitamin D deficiency, and hyperparathyroidism in congestive heart failure.

PURPOSE In contrast to renal and hepatic failure, congestive heart failure (CHF) has not been associated with a defined metabolic bone disorder. However, low bone mass has been reported in patients with CHF who receive a cardiac transplant. Both the pathophysiology and therapy of CHF may influence bone and mineral homeostasis and evidence that calciotropic hormones may affect cardiovascular function is accumulating. Therefore, we evaluated patients with severe CHF to determine the prevalence of osteoporosis and to characterize relationships between mineral homeostasis, bone turnover, bone mass, and severity of CHF. PATIENTS AND METHODS One hundred one patients (79 men and 22 women, aged 25 to 70 years) with severe CHF (New York Heart Association functional class III or IV) referred for consideration for cardiac transplantation were evaluated with measurements of serum 25-hydroxyvitamin D (25-OHD), 1,25 dihydroxyvitamin D [1,25(OH)2D], intact parathyroid hormone (PTH), markers of bone turnover (serum osteocalcin, urinary hydroxyproline, and pyridinium crosslinks); bone mineral density (BMD) by dual energy x-ray absorptiometry was measured in 91 patients. Left ventricular ejection fraction (LVEF) and resting cardiac output (CO) were determined in 88 and maximal treadmill exercise testing and peak oxygen consumption were performed in 45 patients. RESULTS Osteoporosis (T score < or = -2.5) was present in 7% at the lumbar spine, 6% at the total hip, and 19% at the femoral neck. Osteopenia (T scores between -1.0 and -2.5) was present in 43% at the lumbar spine, 47% at the total hip, and 42% at the femoral neck. Women were more severely affected (P = 0.007). Frankly low serum 25-OHD (< or = 9 pg/mL) and 1,25(OH)2D (< or = 15 pg/mL) levels were found in 17% and 26% of the patients, respectively, and elevated serum PTH (> or = 65 pg/mL) in 30%. Both low serum 1,25(OH)2D and increased serum PTH were associated with prerenal azotemia. Low serum vitamin D metabolites were associated with biochemical evidence of increased bone turnover, but BMD did not differ by vitamin D or PTH status. Patients with more severe CHF had significantly lower vitamin D metabolites and higher bone turnover, whereas elevated PTH was associated with better LVEF (21 +/- 1 versus 18 +/- 1%; P = 0.05) and correlated positively with resting CO (R = 0.220; P = 0.04). CONCLUSIONS Osteopenia or osteoporosis were observed in approximately half of these patients with severe CHF. Abnormal calciotropic hormone concentrations, also common, were associated with evidence of increased bone resorption but were not related to BMD in this cross-sectional study. Abnormal concentrations of calciotropic hormones were related to the severity of cardiovascular compromise. Because both low BMD and low serum concentrations of 25-OHD in patients with CHF are associated with higher rates of bone loss and fracture after cardiac transplantation, patients should be evaluated for and receive appropriate therapy for these disorders.

Short-Term Inhibition of Parathyroid Hormone Secretion by a Calcium-Receptor Agonist in Patients with Primary Hyperparathyroidism

BACKGROUND Surgery is the usual therapy for patients with primary hyperparathyroidism. We investigated the ability of a calcimimetic drug that inhibits parathyroid hormone secretion in vitro to decrease serum parathyroid hormone and calcium concentrations in patients with this disorder. METHODS We performed a randomized, placebo-controlled study of single oral doses of 4 to 160 mg of the calcium-receptor agonist drug R-568 in 20 postmenopausal women with mild primary hyperparathyroidism. At base line, the mean (+/-SE) serum calcium concentration was 10.7+/-0.2 mg per deciliter (2.67+/-0.05 mmol per liter). Serum parathyroid hormone and calcium were measured repeatedly after each dose, and safety was assessed. RESULTS Administration of R-568 resulted in a dose-dependent inhibition of parathyroid hormone secretion. The mean serum parathyroid hormone concentration, which was 77+/-11 pg per milliliter (18.8+/-2.7 pmol per liter; normal range, 16 to 65 pg per milliliter [3.9 to 15.9 pmol per liter) at base line, fell by 26+/-8 percent after 20 mg of R-568 (P=0.03), by 42+/-7 percent after 80 mg (P = 0.01), and by 51+/-5 percent after 160 mg (P=0.005). Serum ionized calcium concentrations fell only after the 160-mg dose, with the decrease closely following the decrease in the serum parathyroid hormone concentration. CONCLUSIONS The calcimimetic drug R-568 reduces serum parathyroid hormone and ionized calcium concentrations in postmenopausal women with primary hyperparathyroidism.

The decline in hip bone density after gastric bypass surgery is associated with extent of weight loss.

CONTEXT Bariatric surgery is common and may be associated with deleterious effects on the skeleton. OBJECTIVE Our objective was to assess bone metabolism and bone mineral density (BMD) after Roux-en-Y gastric bypass. DESIGN AND SETTING We conducted a 1-yr prospective longitudinal study at a university hospital bariatric surgery practice and metabolic bone disease unit. PARTICIPANTS Participants included 23 obese (mean body mass index 47 kg/m(2)) men and women, aged 20-64 yr. MAIN OUTCOME MEASURES Serum PTH, 25-hydroxyvitamin D, osteocalcin, and urinary N-telopeptide, and BMD were assessed. RESULTS Patients lost 45 +/- 2 kg 1 yr postoperatively (P < 0.01). PTH increased early (3 months, 43-50 pg/ml; P < 0.001) and urinary calcium dropped (161-92 mg/24 h; P < 0.01), despite doubling of calcium intake (1318-2488 mg/d; P < 0.001). Serum 25-hydroxyvitamin D concentrations were unchanged (23-26 ng/ml), although vitamin D intake increased by 260% (658 IU/d at baseline to 1698 IU/d at 12 months; P < 0.05). Markers of bone remodeling rose (P < 0.01 for both urinary N-telopeptide and osteocalcin), whereas BMD decreased at the femoral neck (9.2%, P < 0.005) and at the total hip (8.0%, P < 0.005). These declines were strongly associated with the extent of weight loss (femoral neck: r = 0.90, P < 0.0001; and total hip: r = 0.65, P = 0.02). Lumbar spine and distal radius sites did not change. CONCLUSIONS After Roux-en-Y gastric bypass, there was evidence of calcium and vitamin D malabsorption. Bone turnover increased, and hip bone density rapidly declined. The decline in hip BMD was strongly associated with weight loss itself. Vigilance for nutritional deficiencies and bone loss in patients both before and after bariatric surgery is crucial.

Osteoporosis after cardiac transplantation

PURPOSE The purpose of this study was to determine the prevalence of osteopenia and fractures and to describe the biochemical indices of mineral metabolism in patients who have undergone cardiac transplantation. PATIENTS AND METHODS Forty adult patients who had received a cardiac transplant between 1982 and 1990 and who were receiving immunosuppressive therapy with prednisone and cyclosporine A were studied. Bone densitometric measurements by dual-energy x-ray absorptiometry of the lumbar spine and femoral neck and radiographs of the thoracic and lumbar spine were obtained for all patients. Routine serum and urine biochemical values as well as more specialized biochemical analyses (intact parathyroid hormone, metabolites of vitamin D, and osteocalcin) were obtained. RESULTS Osteopenia was present in 28% of the patients at the lumbar spine and 20% of the patients at the femoral neck. Vertebral fractures were present in 35% of patients. In contrast to other patients receiving glucocorticoids, serum osteocalcin, a marker of bone formation, was elevated in 60% of patients. CONCLUSIONS Osteopenia and vertebral fractures are common in patients after cardiac transplantation. The presence of elevated osteocalcin levels suggests that the pathogenesis of the osteoporosis in these patients differs from that of glucocorticoid-induced osteoporosis.

Primary hyperparathyroidism: new concepts in clinical, densitometric and biochemical features.

Primary hyperparathyroidism (PHPT) is characterized most commonly now as an asymptomatic disorder with hypercalcaemia and elevated levels of parathyroid hormone (PTH). The elevation in PTH is detected by both the standard immunoradiometric assays (IRMA) and a more recent IRMA that detects only the 1–84 full‐length PTH molecule. The serum calcium concentration is usually <1 mg dL−1 above normal. Recently, another variant of PHPT (normocalcaemic PHPT) has been described in which the serum calcium is normal but the serum PTH is elevated, in the absence of any secondary cause for PTH elevation. Although usually sporadic, PHPT also occurs in inherited syndromes. Skeletal manifestations are appreciated by densitometry showing a typical pattern in which cancellous bone of the lumbar spine is reasonably well preserved whilst the cortical bone of the distal third of the radius is preferentially reduced. Although reduced in incidence, renal stones remain the most common overt complication of PHPT. Other organs are theoretical targets of PHPT such as the neurobehavioural axis and the cardiovascular system. Vitamin D looms as an important determinant of the activity of the PHPT state. The 2002 NIH Workshop on asymptomatic PHPT has led to revised guidelines to help doctors determine who is best advised to have parathyroid surgery and who can be safely followed without surgery. New information about the natural history of PHPT in those who did not undergo surgery has helped to define more precisely who is at‐risk for complications. At the NIH workshop, a number of items were highlighted for further investigation such as pharmacological approaches to controlling hypercalcaemia, elevated PTH levels and maintaining bone density.

Nephrolithiasis and bone involvement in primary hyperparathyroidism

PURPOSE The purpose of this study was to compare patients with primary hyperparathyroidism with and without nephrolithiasis with regard to (1) biochemical profile, and (2) presence and extent of bone involvement. PATIENTS AND METHODS Of 70 unselected patients enrolled in a longitudinal study on the natural history of primary hyperparathyroidism, 62 who underwent complete bone densitometry evaluation were considered. The patients had mild hypercalcemia (2.77 +/- 0.02 mmol/L), as well as elevated parathyroid hormone levels by mid-molecule, N-terminal, and immunoradiometric assays. Bone densitometry was assessed by dual-photon absorptiometry of the lumbar spine and femoral neck, and single-photon absorptiometry of the forearm. RESULTS Eleven of the 62 patients (18%) had nephrolithiasis. There was no difference in serum parathyroid hormone levels, calcium, phosphorus, serum 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D3 between those with and without kidney stones. Total daily urinary calcium excretion was higher among those who formed stones (8.2 +/- 1.0 mmol versus 6.1 +/- 0.4 mmol, p less than 0.05), but not when expressed per mmol of creatinine (0.72 +/- 0.07 versus 0.69 +/- 0.04). Urinary hydroxyproline was also higher in patients who formed stones (58 +/- 11 mg/24 hours versus 37 +/- 2 mg/24 hours; p less than 0.05). Hypercalciuria occurred in 39% of the entire cohort (n = 24), and in 33% (n = 17) of those without stones. Only 29% (n = 7) of those with hypercalciuria had nephrolithiasis. Calcium excretion correlated positively with serum 1,25-dihydroxyvitamin D3 (r = +0.32, p less than 0.05), and negatively with forearm bone mineral density (all patients: r = -0.34, p less than 0.05; hypercalciuric patients: r = -0.53, p less than 0.05). Circulating 1,25-dihydroxyvitamin D3 levels were elevated in a similar proportion of (1) all patients (31%, n = 19); (2) those with nephrolithiasis (27%); and (3) those without stones (31%). Bone mineral density was less than 80% of normal in 61% of patients, but forearm, femoral neck, and lumbar spine density were indistinguishable among those with and without stones. CONCLUSIONS Cortical bone demineralization occurs to the same extent and frequency in patients with and without nephrolithiasis, and these two subgroups share similar biochemical and bone densitometric profiles. The pathophysiologic events leading to renal and skeletal involvement in primary hyperparathyroidism may be less selective than previously believed, as evidenced by: (1) increased urinary hydroxyproline in patients with nephrolithiasis, and (2) documentation that urinary calcium excretion reflects not only vitamin D status, but bone resorption was well.

2,3-dimercaptosuccinic acid as an antidote for lead intoxication

2,3‐Dimercaptosuccinic acid (DMSA) is an orally effective drug more specific and with a wider therapeutic index than currently available drugs for lead intoxication. Eighteen men with elevated blood lead (BPb) concentrations received either 30, 20, or 10 mg/kg DMSA for 5 days in three divided daily doses. The mean BPb level decreased 72.5%, 58.3%, and 35.5% of the pretreatment values, with a simultaneous elevation in urinary Pb excretion. Clinical symptoms and biochemical indices of lead toxicity also improved. Red blood cell d‐aminolevulinic acid dehydratase activity increased, while urinary excretion of d‐aminolevulinic acid and coproporphyrin fell. DMSA was well tolerated; the only observed adverse drug reaction was a mild, transient elevation of serum SGPT levels in two subjects. DMSA appears promising and may greatly simplify the treatment of lead intoxication.