Anna Kepley

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.

Abnormalities in Cortical Bone, Trabecular Plates, and Stiffness in Postmenopausal Women Treated With Glucocorticoids

CONTEXT The mechanisms by which glucocorticoids (GCs) increase skeletal fragility are not well understood. OBJECTIVE The objective of the study was to evaluate the microarchitecture, trabecular morphology, and biomechanical properties of bone in postmenopausal women treated with GCs. DESIGN This was a case-control study. SETTING The study was conducted at a university hospital outpatient facility. PATIENTS Postmenopausal women treated with oral GCs for longer than 3 months (n = 30) and age/race-matched controls (n = 60) participated in the study. MAIN OUTCOME MEASURES Areal bone mineral density aBMD (BMD) by dual-energy x-ray absorptiometry (DXA) was measured. Trabecular and cortical volumetric BMD (vBMD) and microarchitecture by high-resolution peripheral computed tomography of the distal radius and tibia were also measured. Whole-bone stiffness was estimated by finite element analysis. A novel technique, individual trabecula segmentation, was used to evaluate trabecular type (as plate or rod), orientation, and connectivity. RESULTS DXA T-scores did not differ significantly at any site. GC subjects had significantly lower total, cortical, and trabecular vBMD and thinner cortices, fewer, thinner, more widely, and irregularly spaced trabeculae. They had fewer trabecular plates, fewer axially aligned trabeculae, and lower trabecular connectivity. Differences ranged from 4% to 65% for these trabecular measures and 5% to 17% for the cortical measures. Whole-bone stiffness was significantly lower (11%-16%) in GC subjects. Markers of bone formation (osteocalcin and amino-terminal propeptide of type I procollagen) and resorption (C-telopeptide) were lower in the GC subjects. CONCLUSIONS Despite similar areal BMD by DXA, GC-treated women had abnormal cortical and trabecular vBMD and microarchitecture at both the radius and tibia, including fewer trabecular plates, a less axially aligned trabecular network, lower trabecular connectivity, thinner cortices, and lower whole-bone stiffness. Further research into these abnormalities as mechanisms for fracture in GC-treated women is warranted.

Vitamin D in Primary Hyperparathyroidism: Effects on Clinical, Biochemical, and Densitometric Presentation

CONTEXT Vitamin D (25-hydroxyvitamin D [25OHD]) deficiency (<20 ng/mL) and insufficiency (20-29 ng/mL) are common in primary hyperparathyroidism (PHPT), but data regarding their skeletal effects in PHPT are limited. OBJECTIVE The objective was to evaluate the association between 25OHD levels and PHPT severity. DESIGN, SETTINGS, AND PARTICIPANTS This is a cross-sectional analysis of 100 PHPT patients with and without 25OHD insufficiency and deficiency from a university hospital setting. OUTCOME MEASURES We measured calciotropic hormones, bone turnover markers, and bone mineral density (BMD) by dual x-ray absorptiometry. RESULTS Lower 25OHD was associated with some (PTH: r = -0.42; P < .0001; 1,25-dihydroxyvitamin D: r = -0.27; P = .008; serum PO4: r = 0.31; P = .002) but not all (serum/urine calcium) indicators of PHPT severity. Lower 25OHD was also associated with younger age, higher body mass index, male gender, better renal function, and lower vitamin D intake. Comparison of those with deficient (<20 ng/mL; 19%) vs insufficient (20-29 ng/mL; 35%) vs replete (≥30 ng/mL; 46%) 25OHD demonstrated more severe PHPT as reflected by higher PTH (mean ± SEM, 126 ± 10 vs 81 ± 7 vs 72 ± 7 pg/mL; P < .0001) but no difference in nephrolithiasis, osteoporosis, fractures, serum or urinary calcium, bone turnover markers, or BMD after adjustment for age and weight. In women, T-scores at the 1/3 radius were lower in those with 25OHD of 20-29 ng/mL, compared to those who were vitamin D replete (P = .048). In multiple regression modeling, 25OHD (but not PTH) was an independent predictor of 1/3 radius BMD. CONCLUSION Vitamin D deficiency is associated with more severe PHPT as reflected by PTH levels, but effects on BMD are limited to the cortical 1/3 radius and are quite modest. These data support international guidelines that consider PHPT patients with 25OHD <20 ng/mL to be deficient. However, in this cohort with few profoundly vitamin D-deficient patients, vitamin D status did not appear to significantly impact clinical presentation or bone density.

Predictors of Renal Function in Primary Hyperparathyroidism

CONTEXT Current guidelines for parathyroidectomy in primary hyperparathyroidism (PHPT) include an estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m(2). Although the biochemical abnormalities associated with PHPT could impair renal function, there are currently no data examining whether more severe hypercalcemia, hypercalciuria, or nephrolithiasis are associated with chronic kidney disease (CKD) in mild PHPT. OBJECTIVE This cross-sectional study evaluated predictors of renal function in PHPT. DESIGN This is a case series of PHPT patients with (eGFR < 60 mL/min per 1.73 m(2)) and without (eGFR ≥ 60 mL/min per 1.73 m(2)) CKD. SETTINGS AND PARTICIPANTS We studied 114 PHPT patients in a university hospital setting. OUTCOME MEASURES We identified predictors of renal function using multiple linear regression. RESULTS eGFR was associated with age, hypertension, antihypertensive medication use, fasting glucose, and 25-hydroxyvitamin D. eGFR was positively rather than negatively associated with several PHPT disease severity indices including history of nephrolithiasis, 24-hour urinary calcium excretion, and 1,25-dihydroxyvitamin D but not serum calcium or PTH levels. An eGFR less than 60 mL/min per 1.73 m(2) was observed in 15% (n = 17), all of whom had stage 3 CKD (eGFR 30-59 mL/min per 1.73 m(2)). Those with CKD were older, had higher 25-hydroxyvitamin D levels and lower 1,25-dihydroxyvitamin D levels, and were more likely to be hypertensive than those without CKD. There were no between-group (<60 vs ≥60 mL/min per 1.73 m(2)) differences in serum calcium, PTH, nephrolithiasis, or meeting surgical criteria other than eGFR. Multiple linear regression indicated that age and diastolic blood pressure were negatively associated with eGFR, whereas serum calcium, kidney stones, and alcohol use were positive predictors. Calculation of eGFR using either the Modification of Diet in Renal Disease or Chronic Kidney Disease Epidemiology Collaboration equation yielded similar results. CONCLUSIONS PHPT patients with stage 3 CKD do not have biochemical or clinical evidence of more severe hyperparathyroidism compared with those without CKD. Traditional risk factors, rather than clinical or biochemical indices of PHPT, are associated with lower eGFR in mild PHPT.

Marrow adiposity assessed on transiliac crest biopsy samples correlates with noninvasive measurement of marrow adiposity by proton magnetic resonance spectroscopy ( 1 H-MRS) at the spine but not the femur

SummaryMeasurement of marrow fat (MF) is important to the study of bone fragility. We measured MF on iliac biopsies and by spine/hip magnetic resonance spectroscopy in the same subjects. Noninvasively assessed spine MF and histomorphometrically assessed MF correlated well. MF quantity and relationships with bone volume differed by measurement site.IntroductionExcess marrow fat has been implicated in the pathogenesis of osteoporosis in several populations. In the bone marrow, adipocytes and osteoblasts share a common precursor and are reciprocally regulated. In addition, adipocytes may secrete toxic fatty acids and adipokines that adversely affect osteoblasts. Measurement of marrow fat is important to the study of mechanisms of bone fragility. Marrow fat can be quantified on bone biopsy samples by histomorphometry and noninvasively by proton magnetic resonance spectroscopy (1H-MRS). In this study, we evaluate relationships between marrow fat assessed using both methods in the same subjects for the first time.MethodsSixteen premenopausal women, nine with idiopathic osteoporosis and seven normal controls, had marrow fat measured at the iliac crest by bone biopsy and at the lumbar spine (L3) and proximal femur by 1H-MRS.ResultsAt L3, fat fraction by 1H-MRS correlated directly and significantly with marrow fat variables on iliac crest biopsies (r = 0.5–0.8). In contrast, there were no significant correlations between fat fraction at the femur and marrow fat on biopsies. Marrow fat quantity (%) was greater at the femur than at L3 and the iliac crest and correlated inversely with total hip and femoral neck BMD by DXA.ConclusionsIn summary, measurement of marrow fat in transiliac crest biopsies correlates with marrow fat at the spine but not the proximal femur by 1H-MRS. There were site-specific differences in marrow fat quantity and in the relationships between marrow fat and bone volume.

Effect of Low Vitamin D on Volumetric Bone Mineral Density, Bone Microarchitecture, and Stiffness in Primary Hyperparathyroidism

CONTEXT Patients with 25-hydroxyvitamin D deficiency (25OHD <20 ng/ml) and primary hyperparathyroidism (PHPT) have more severe disease reflected by higher serum PTH levels compared to those with vitamin D levels in the insufficient (20-29 ng/ml) or replete range (≥ 30 ng/ml). OBJECTIVE To study the effect of low vitamin D in PHPT on volumetric bone mineral density (vBMD), bone microarchitecture, and bone strength. DESIGN, SETTING, AND PARTICIPANTS This is a cross-sectional analysis of 99 PHPT patients with and without 25OHD insufficiency and deficiency from a university hospital. OUTCOME MEASURES Bone microarchitecture and strength were assessed with high-resolution peripheral quantitative computed tomography (HRpQCT), microfinite element analysis, and individual trabecula segmentation. RESULTS In this cohort, 25OHD levels were deficient in 18.1%, insufficient in 35.4% and replete in 46.5%. Those with lower 25OHD levels had higher PTH (P < .0001), were younger (P = .001) and tended to weigh more (P = .053). There were no age-, weight- and sex-adjusted between-group differences (<20 vs 20-29 vs ≥ 30 ng/ml) in any HRpQCT, microfinite element analysis, or individual trabecula segmentation indices. Because few participants had 25OHD below 20 ng/ml, we also compared those with 25OHD below 30 vs at least 30 ng/ml and found only a trend toward lower adjusted cortical vBMD (3.1%, P = .08) and higher cortical porosity (least squares mean ± SEM 7.5 ± 0.3 vs 6.6 ± 0.3%, P = .07) at the tibia but not the radius. Stiffness did not differ at either site. In multiple regression analysis, 25OHD accounted for only three of the 49.2% known variance in cortical vBMD; 25OHD was not significant in the model for cortical porosity at the tibia. CONCLUSION Low 25OHD levels are associated with higher PTH levels in PHPT, but contrary to our hypothesis, these differences did not significantly affect vBMD or microarchitecture, nor did they result in lower stiffness. Low vitamin D in PHPT using current 25OHD thresholds for insufficiency and deficiency did not significantly affect skeletal integrity as assessed by HRpQCT.

Seasonal Variability in Vitamin D Levels No Longer Detectable in Primary Hyperparathyroidism.

CONTEXT Seasonal variability in 25-hydroxyvitamin D [25(OH)D] and PTH levels in the general population has been associated with differences in bone turnover markers, bone density, and fracture risk. Seasonal variability in 25(OH)D and PTH levels has also been reported in primary hyperparathyroidism (PHPT). OBJECTIVE Given the widespread use of vitamin D supplements, we sought to determine whether patients with PHPT still demonstrated seasonal variation in 25(OH)D levels. DESIGN AND SETTING This cross-sectional study was conducted at a university medical center at a Northeastern U.S. latitude (New York, NY). PATIENTS One hundred patients with PHPT participated in the study. OUTCOME MEASURES We assessed vitamin D supplement use and seasonal variation in serum 25(OH)D. RESULTS Patients had PHPT ([mean ± SD] calcium, 10.8 ± 1.0 mg/dL; PTH, 85 ± 48 pg/mL) with a mean 25(OH)D level of 29 ± 10 ng/mL. Although only one fifth of participants had vitamin D deficiency (19% < 20 ng/mL), more than half were either deficient or insufficient (54% < 30 ng/mL). Sun exposure varied by season, but there were no seasonal differences in levels of 25(OH)D, PTH, bone markers, or bone mineral density, or in the prevalence of 25(OH)D less than 20 or less than 30 ng/mL. Most of the participants (65%) took supplemental vitamin D (dose among users: mean, 1643 ± 1496 IU; median, 1000 IU daily), and supplement users had markedly better vitamin D status than nonusers (25(OH)D < 20 ng/mL: 8 vs 40%; P < .0001; < 30 ng/mL: 40 vs 80%; P = .0001; ≥ 30 ng/mL: 60 vs 20%; P = .0001). CONCLUSIONS We found no evidence of seasonal variation in 25(OH)D levels or PHPT disease severity in the Northeastern United States. This change is likely due to widespread high vitamin D supplement intake, which has resulted in better vitamin D status among supplement users and can mask the effect of season on serum 25(OH)D levels.

Adults with cystic fibrosis have deficits in bone structure and strength at the distal tibia despite similar size and measuring standard and relative sites

Individuals with cystic fibrosis (CF) have lower bone mineral density (BMD) by DXA and are at higher risk of fracture than healthy controls. However, the 2-dimensional measurement of areal BMD (aBMD) provided by DXA is influenced by bone size and the true extent of the bone deficit is unclear. Our objective was to use high-resolution peripheral quantitative computed tomography (HR-pQCT) and individual trabecula segmentation (ITS) analysis to compare volumetric BMD (vBMD), microarchitecture and estimated strength at the distal radius and tibia in 26 young adults with CF and 26 controls matched for age, gender, and race. To assess the effect of limb length and minimize the confounding effects of size on HR-pQCT outcomes, we scanned participants at both the standard fixed HR-pQCT measurement sites and at a subject-specific relative site that varied according to limb length. CF participants did not differ significantly in age, height, weight, or BMI from controls. Ulnar and tibial lengths were 9mm shorter in CF patients, though differences were not significant. CF patients had significantly lower BMI-adjusted aBMD by DXA at the lumbar spine (8.9%, p<0.01), total hip (11.5%, p<0.01) and femoral neck (14.5%, p<0.01), but not at the forearm. At the fixed radius site, thickness of trabecular plates and torsional stiffness were significantly lower in CF participants than controls. At the relative radius site, only torsional stiffness was significantly lower in CF participants. At the tibia, total, trabecular and cortical vBMD were significantly lower at both fixed and relative sites in CF participants, with fewer, more widely-spaced trabecular plates, lower trabecular connectivity, and lower axial and torsional stiffness. Our results confirm that aBMD is lower at the spine and hip in young adults with CF, independent of BMI and body size. We also conclude that vBMD and stiffness are lower at the weight-bearing tibia. The pathogenesis of these differences in bone density and strength at the tibia appear to be related to trabecular drop-out and reduced trabecular connectivity and to be independent of differences in limb length, as assessed by scanning participants at both standard and relative sites. We concluded that significant deficits in bone structure and strength persist in young adults with CF, despite advances in care that permit them to attain relatively normal height and weight.