Marcella D. Walker

Current Issues in the Presentation of Asymptomatic Primary Hyperparathyroidism: Proceedings of the Fourth International Workshop

OBJECTIVE This report summarizes data on traditional and nontraditional manifestations of primary hyperparathyroidism (PHPT) that have been published since the last International Workshop on PHPT. PARTICIPANTS This subgroup was constituted by the Steering Committee to address key questions related to the presentation of PHPT. Consensus was established at a closed meeting of the Expert Panel that followed. EVIDENCE Data from the 5-year period between 2008 and 2013 were presented and discussed to determine whether they support changes in recommendations for surgery or nonsurgical follow-up. CONSENSUS PROCESS Questions were developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies was undertaken. After extensive review and discussion, the subgroup came to agreement on what changes in the recommendations for surgery or nonsurgical follow-up of asymptomatic PHPT should be made to the Expert Panel. CONCLUSIONS 1) There are limited new data available on the natural history of asymptomatic PHPT. Although recognition of normocalcemic PHPT (normal serum calcium with elevated PTH concentrations; no secondary cause for hyperparathyroidism) is increasing, data on the clinical presentation and natural history of this phenotype are limited. 2) Although there are geographic differences in the predominant phenotypes of PHPT (symptomatic, asymptomatic, normocalcemic), they do not justify geography-specific management guidelines. 3) Recent data using newer, higher resolution imaging and analytic methods have revealed that in asymptomatic PHPT, both trabecular bone and cortical bone are affected. 4) Clinically silent nephrolithiasis and nephrocalcinosis can be detected by renal imaging and should be listed as a new criterion for surgery. 5) Current data do not support a cardiovascular evaluation or surgery for the purpose of improving cardiovascular markers, anatomical or functional abnormalities. 6) Some patients with mild PHPT have neuropsychological complaints and cognitive abnormalities, and some of these patients may benefit from surgical intervention. However, it is not possible at this time to predict which patients with neuropsychological complaints or cognitive issues will improve after successful parathyroid surgery.

Carotid Vascular Abnormalities in Primary Hyperparathyroidism

CONTEXT Data on the presence, extent, and reversibility of cardiovascular disease in primary hyperparathyroidism (PHPT) are conflicting. OBJECTIVE This study evaluated carotid structure and function in PHPT patients compared with population-based controls. DESIGN This is a case-control study. SETTING The study was conducted in a university hospital metabolic bone disease unit. PARTICIPANTS Forty-nine men and women with PHPT and 991 controls without PHPT were studied. OUTCOME MEASURES We measured carotid intima-media thickness (IMT), carotid plaque presence and thickness, and carotid stiffness, strain, and distensibility. RESULTS IMT, carotid plaque thickness, carotid stiffness, and distensibility were abnormal in PHPT patients, and IMT was higher in patients than controls (0.959 vs. 0.907 mm, P < 0.0001). In PHPT, PTH levels, but not calcium concentration, predicted carotid stiffness (P = 0.04), strain (P = 0.06), and distensibility (P = 0.07). Patients with increased carotid stiffness had significantly higher PTH levels than did those with normal stiffness (141 +/- 48 vs. 94.9 +/- 44 pg/ml, P = 0.002), and odds of abnormal stiffness increased 1.91 (confidence interval = 1.09-3.35; P = 0.024) for every 10 pg/ml increase in PTH, adjusted for age, creatinine, and albumin-corrected calcium. CONCLUSIONS Mild PHPT is associated with subclinical carotid vascular manifestations. IMT, a predictor of cardiovascular outcomes, is increased. Measures of carotid stiffness are associated with extent of PTH elevation, suggesting that those with more severe PHPT may have impaired vascular compliance and that PTH, rather than calcium, is the mediator.

Neuropsychological Features in Primary Hyperparathyroidism: A Prospective Study

CONTEXT Data regarding the presence, extent, and reversibility of psychological and cognitive features of primary hyperparathyroidism (PHPT) are conflicting. OBJECTIVE This study evaluated psychological symptoms and cognitive function in PHPT. DESIGN This is a case-control study in which symptoms and their improvement 6 months after surgical cure of PHPT were assessed. SETTINGS The study was conducted in a university hospital metabolic bone disease unit and endocrine surgery practice. PARTICIPANTS Thirty-nine postmenopausal women with PHPT and 89 postmenopausal controls without PHPT participated in the study. INTERVENTION Participants with PHPT underwent parathyroidectomy. OUTCOME MEASURES Measurements used in the study were: Beck Depression Inventory (BDI); State-Trait Anxiety Inventory, Form Y (STAI-Y); North American Adult Reading Test (NAART); Wechsler Memory Scale Logical Memory Test, Russell revision (LM); Buschke Selective Reminding Test (SRT); Rey Visual Design Learning Test (RVDLT); Booklet Category Test, Victoria revision (BCT); Rosen Target Detection Test (RTD); Wechsler Adult Intelligence Scale-Revised Digit Symbol Subtest (DSy); Wechsler Adult Intelligence Scale Digit Span Subtest (DSpan). RESULTS At baseline, women with PHPT had significantly higher symptom scores for depression and anxiety than controls and worse performance on tests of verbal memory (LM and SRT) and nonverbal abstraction (BCT). Depressive symptoms, nonverbal abstraction, and some aspects of verbal memory (LM) improved after parathyroidectomy to the extent that scores in these domains were no longer different from controls. Baseline differences and postoperative improvement in cognitive measures were independent of anxiety and depressive symptoms and were not linearly associated with serum levels of calcium or PTH. CONCLUSIONS Mild PHPT is associated with cognitive features affecting verbal memory and nonverbal abstraction that improve after parathyroidectomy.

Vitamin D deficiency is associated with subclinical carotid atherosclerosis: the Northern Manhattan Study

Background and Purpose— The purpose of this study was to assess the association of vitamin D deficiency and indices of mineral metabolism with subclinical carotid markers that predict cardiovascular events. Methods— Two hundred three community-dwelling adults (Northern Manhattan Study; age, 68±11; age range, 50 to 93 years) had serum measurements (calcium, phosphorus, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, parathyroid hormone) and carotid ultrasound (plaque presence, number, maximal carotid plaque thickness, intima-media thickness). Results— Adjusting for cardiovascular risk factors, plaque number was associated with phosphorus levels (&bgr;=0.39 per 1-mg/dL increase; P=0.02) and calcium–phosphorus product (&bgr;=0.36 per 10-U increase; P=0.03). In those with plaque (N=116 [57%]), the association of plaque number with phosphorus and calcium–phosphorus product persisted. In addition, 25-hydroxyvitamin D was inversely associated with both intima-media thickness (&bgr;=−0.01 per 10-ng/mL increase; P=0.05) and maximal carotid plaque thickness (&bgr;=−0.10 per 10-ng/mL increase; P=0.03). In a model containing traditional cardiac risk factors and indices of mineral metabolism, 25-hydroxyvitamin D accounted for 13% of the variance in both intima-media thickness and maximal carotid plaque thickness. Calcium, parathyroid hormone, and 1,25-dihydroxyvitamin D levels were not associated with carotid measures. Conclusions— After adjusting for cardiovascular risk factors and renal function, serum phosphorus and calcium–phosphorus product were associated with a greater burden of subclinical carotid atherosclerosis. Low 25-hydroxyvitamin D levels were associated with increased intima-media thickness and maximal carotid plaque thickness in those with plaque, and 25-hydroxyvitamin D contributed in a robust manner to the variance in both. These results confirm and extend data on the association of low vitamin D levels with subclinical carotid atherosclerosis. The precise nature of this association and the optimum levels of vitamin D for vascular health remain to be elucidated.

Better skeletal microstructure confers greater mechanical advantages in Chinese-American women versus white women

Despite lower areal bone mineral density (aBMD), Chinese‐American women have fewer fractures than white women. We hypothesized that better skeletal microstructure in Chinese‐American women in part could account for this paradox. Individual trabecula segmentation (ITS), a novel image‐analysis technique, and micro–finite‐element analysis (µFEA) were applied to high‐resolution peripheral quantitative computed tomography (HR‐pQCT) images to determine bone microarchitecture and strength in premenopausal Chinese‐American and white women. Chinese‐American women had 95% and 80% higher plate bone volume fraction at the distal radius and tibia, respectively, as well as 20% and 18% higher plate number density compared with white women (p < .001). With similar rodlike characteristics, the plate‐to‐rod ratio was twice as high in the Chinese‐American than in white trabecular bone (p < .001). Plate‐rod junction density, a parameter indicating trabecular network connections, was 37% and 29% greater at the distal radius and tibia, respectively, in Chinese‐American women (p < .002). Moreover, the orientation of the trabecular bone network was more axially aligned in Chinese‐American women because axial bone volume fraction was 51% and 32% higher at the distal radius and tibia, respectively, than in white women (p < .001). These striking differences in trabecular bone microstructure translated into 55% to 68% (distal radius, p < .001) and 29% to 43% (distal tibia, p < .01) greater trabecular bone strength, as assessed by Youngs moduli, in the Chinese‐American versus the white group. The observation that Chinese‐American women have a major microstructural advantage over white women may help to explain why their risk of fracture is lower despite their lower BMD.

Application of high-resolution skeletal imaging to measurements of volumetric BMD and skeletal microarchitecture in Chinese-American and white women: explanation of a paradox.

Asian women have lower rates of hip and forearm fractures despite lower areal BMD (aBMD) by DXA compared with white women and other racial groups. We hypothesized that the lower fracture rates may be explained by more favorable measurements of volumetric BMD (vBMD) and microarchitectural properties, despite lower areal BMD. To address this hypothesis, we used high‐resolution pQCT (HRpQCT), a new method that can provide this information noninvasively. We studied 63 premenopausal Chinese‐American (n = 31) and white (n = 32) women with DXA and HRpQCT. aBMD by DXA did not differ between groups for the lumbar spine (1.017 ± 0.108 versus 1.028 ± 0.152 g/cm2; p = 0.7), total hip (0.910 ± 0.093 versus 0.932 ± 0.134 g/cm2; p = 0.5), femoral neck (0.788 ± 0.083 versus 0.809 ± 0.129 g/cm2; p = 0.4), or one‐third radius (0.691 ± 0.052 versus 0.708 ± 0.047 g/cm2; p = 0.2). HRpQCT at the radius indicated greater trabecular (168 ± 41 versus 137 ± 33 mg HA/cm3; p = <0.01) and cortical (963 ± 46 versus 915 ± 42 mg HA/cm3; p < 0.0001) density; trabecular bone to tissue volume (0.140 ± 0.034 versus 0.114 ± 0.028; p = <0.01); trabecular (0.075 ± 0.013 versus 0.062 ± 0.009 mm; p < 0.0001) and cortical thickness (0.98 ± 0.16 versus 0.80 ± 0.14 mm; p < 0.0001); and lower total bone area (197 ± 34 versus 232 ± 33 mm2; p = <0.001) in the Chinese versus white women and no difference in trabecular number, spacing, or inhomogeneity before adjustment for covariates. Similar results were observed at the weight‐bearing tibia. At the radius, adjustment for covariates did not change the direction or significance of differences except for bone, which became similar between the groups. However, at the tibia, adjustment for covariates attenuated differences in cortical BMD and bone area and accentuated differences in trabecular microarchitecture such that Chinese women additionally had higher trabecular number and lower trabecular spacing, as well as inhomogeneity after adjustment. Using the high‐resolution technology, the results provide a mechanistic explanation for why Chinese women have fewer hip and forearm fractures than white women.

Differences in Bone Microarchitecture Between Postmenopausal Chinese-American and White Women

Chinese‐American women have lower rates of hip and forearm fracture than white women despite lower areal bone density (aBMD) by dual X‐ray absorptiometry (DXA). We recently reported higher trabecular (Dtrab) and cortical (Dcomp) bone density as well as greater trabecular (Tb.Th) and cortical thickness (C.Th) but smaller bone area (CSA), as measured by high‐resolution peripheral quantitative computed tomography (HR‐pQCT), in premenopausal Chinese‐American compared with white women. These findings may help to account for the lower fracture rate among Chinese‐American women but were limited to measurements in premenopausal women. This study was designed to extend these investigations to postmenopausal Chinese‐American (n = 29) and white (n = 68) women. Radius CSA was 10% smaller in the Chinese‐American versus the white group (p = .008), whereas their C.Th and Dcomp values were 18% and 6% greater (p < .001 for both). Tibial HR‐pQCT results for cortical bone were similar to the radius, but Tb.Th was 11% greater in Chinese‐American versus white women (p = .007). Tibial trabecular number and spacing were 17% lower and 20% greater, respectively, in Chinese‐American women (p < .0001 for both). There were no differences in trabecular or whole‐bone stiffness estimated by microstructural finite‐element analysis, but Chinese‐American women had a greater percentage of load carried by the cortical bone compartment at the distal radius and tibia. There was no difference in load distribution at the proximal radius or tibia. Whole‐bone finite‐element analysis may indicate that the thicker, more dense cortical bone and thicker trabeculae in postmenopausal Chinese‐American women compensate for fewer trabeculae and smaller bone size.

Aortic Valve Calcification in Mild Primary Hyperparathyroidism

CONTEXT It is unclear whether cardiovascular disease is present in primary hyperparathyroidism (PHPT). OBJECTIVE Aortic valve structure and function were compared in PHPT patients and population-based controls. DESIGN This is a case-control study. SETTING The study was conducted in a university hospital metabolic bone disease unit. PARTICIPANTS We studied 51 patients with PHPT and 49 controls. OUTCOME MEASURES We measured the aortic valve calcification area and the transaortic pressure gradient. RESULTS Aortic valve calcification area was significantly higher in PHPT (0.24 ± 0.02 vs. 0.17 ± 0.02 cm(2), p<0.01), although there was no difference in the peak transaortic pressure gradient, a functional measure of valvular calcification (5.6 ± 0.3 vs. 6.0 ± 0.3 mm Hg, P = 0.39). Aortic valve calcification area was positively associated with PTH (r = 0.34; P < 0.05) but not with serum calcium, phosphorus, or 25-hydroxyvitamin D levels or with calcium-phosphate product. Serum PTH level remained an independent predictor of aortic valve calcification area after adjustment for age, sex, body mass index, smoking status, history of hypercholesterolemia and hypertension, and estimated glomerular filtration rate. CONCLUSIONS Mild PHPT is associated with subclinical aortic valve calcification. PTH, but not serum calcium concentration, predicted aortic valve calcification. PTH was a more important predictor of aortic valve calcification than well-accepted cardiovascular risk factors.

Skeletal structure in postmenopausal women with osteopenia and fractures is characterized by abnormal trabecular plates and cortical thinning.

The majority of fragility fractures occur in women with osteopenia rather than osteoporosis as determined by dual‐energy X‐ray absorptiometry (DXA). However, it is difficult to identify which women with osteopenia are at greatest risk. We performed this study to determine whether osteopenic women with and without fractures had differences in trabecular morphology and biomechanical properties of bone. We hypothesized that women with fractures would have fewer trabecular plates, less trabecular connectivity, and lower stiffness. We enrolled 117 postmenopausal women with osteopenia by DXA (mean age 66 years; 58 with fragility fractures and 59 nonfractured controls). All had areal bone mineral density (aBMD) measured by DXA. Trabecular and cortical volumetric bone mineral density (vBMD), trabecular microarchitecture, and cortical porosity were measured by high‐resolution peripheral computed tomography (HR‐pQCT) of the distal radius and tibia. HR‐pQCT scans were subjected to finite element analysis to estimate whole bone stiffness and individual trabecula segmentation (ITS) to evaluate trabecular type (as plate or rod), orientation, and connectivity. Groups had similar age, race, body mass index (BMI), and mean T‐scores. Fracture subjects had lower cortical and trabecular vBMD, thinner cortices, and thinner, more widely separated trabeculae. By ITS, fracture subjects had fewer trabecular plates, less axially aligned trabeculae, and less trabecular connectivity. Whole bone stiffness was lower in women with fractures. Cortical porosity did not differ. Differences in cortical bone were found at both sites, whereas trabecular differences were more pronounced at the radius. In summary, postmenopausal women with osteopenia and fractures had lower cortical and trabecular vBMD; thinner, more widely separated and rodlike trabecular structure; less trabecular connectivity; and lower whole bone stiffness compared with controls, despite similar aBMD by DXA. Our results suggest that in addition to trabecular and cortical bone loss, changes in plate and rod structure may be important mechanisms of fracture in postmenopausal women with osteopenia.

Effect of parathyroidectomy on subclinical cardiovascular disease in mild primary hyperparathyroidism

OBJECTIVE We recently demonstrated that mild primary hyperparathyroidism (PHPT) is associated with increased carotid intima-media thickness (IMT) and stiffness, and increased aortic valve calcification. It is unclear whether parathyroidectomy (PTX) improves these abnormalities. The purpose of this study was to determine whether cardiovascular abnormalities in PHPT improve with PTX. DESIGN Forty-four patients with PHPT were studied using carotid ultrasound and transthoracic echocardiography before and after PTX. Carotid IMT, carotid plaque and stiffness, left ventricular mass index (LVMI), myocardial and valvular calcification, and diastolic function were measured before, 1- and 2-year post-PTX. RESULTS Two years after PTX, increased carotid stiffness tended to decline to the normal range (17%, P=0.056) while elevated carotid IMT did not improve. Carotid plaque number and thickness, LVMI and cardiac calcifications did not change after PTX, while some measures of diastolic function (isovolumic relaxation time (IVRT) and tissue Doppler peak early diastolic velocity) worsened within the normal range. Indices did improve in patients with cardiovascular abnormalities at baseline. Increased carotid stiffness improved by 28% (P=0.004), a decline likely to be of clinical significance. More limited improvements also occurred in elevated IMT (3%, P=0.017) and abnormal IVRT (13%, P<0.05), a measure of diastolic dysfunction. CONCLUSIONS In mild PHPT, PTX led to modest changes in some cardiovascular indices. Improvements were mainly evident in those with preexisting cardiovascular abnormalities, particularly elevated carotid stiffness. These findings are reassuring with regard to current international guidelines that do not include cardiovascular disease as a criterion for PTX.