In premenopausal women with idiopathic osteoporosis, lower bone formation rate is associated with higher body fat and higher IGF-1.

We examined serum IGF-1 in premenopausal IOP, finding relationships that were opposite to those expected: higher IGF-1 was associated with lower bone formation and higher body fat, and lower BMD response to teriparatide. These paradoxical relationships between serum IGF-1, bone, and fat may contribute to the mechanism of idiopathic osteoporosis in premenopausal women. INTRODUCTION: Premenopausal women with idiopathic osteoporosis (IOP) have marked deficits in bone microarchitecture but variable bone remodeling. We previously reported that those with low tissue-level bone formation rate (BFR) are less responsive to teriparatide and have higher serum IGF-1, a hormone anabolic for osteoblasts and other tissues. The IGF-1 data were unexpected because IGF-1 is low in other forms of low turnover osteoporosis-leading us to hypothesize that IGF-1 relationships are paradoxical in IOP. This study aimed to determine whether IOP women with low BFR have higher IGF-1 and paradoxical IGF-1 relationships in skeletal and non-skeletal tissues, and whether IGF-1 and the related measures predict teriparatide response. METHODS: This research is an ancillary study to a 24 month clinical trial of teriparatide for IOP. Baseline assessments were related to trial outcomes: BMD, bone remodeling. SUBJECTS:  Premenopausal women with IOP(n = 34); bone remodeling status was defined by baseline cancellous BFR/BS on bone biopsy. MEASURES:  Serum IGF-1 parameters, compartmental adiposity (DXA, CT, MRI), serum hormones, and cardiovascular-risk-markers related to fat distribution. RESULTS: As seen in other populations, lower BFR was associated with higher body fat and poorer teriparatide response. However, in contrast to observations in other populations, low BFR, higher body fat, and poorer teriparatide response were all related to higher IGF-1: IGF-1 Z-score was inversely related to BFR at all bone surfaces (r = - 0.39 to - 0.46; p < 0.05), directly related to central fat (p = 0.05) and leptin (p = 0.03). IGF-1 inversely related to 24 month hip BMD %change (r = - 0.46; p = 0.01). CONCLUSIONS: Paradoxical IGF-1 relationships suggest that abnormal or atypical regulation of bone and fat may contribute to osteoporosis mechanisms in premenopausal IOP.

Cognition and cerebrovascular function in primary hyperparathyroidism before and after parathyroidectomy.

PURPOSE: There are cognitive changes in primary hyperparathyroidism (PHPT) that improve with parathyroidectomy, but the mechanism of cognitive dysfunction has not been delineated. We assessed if cerebrovascular function is impaired in PHPT, improves post-parathyroidectomy and is associated with PTH level and cognitive dysfunction. METHODS: This is an observational study of 43 patients with mild hypercalcemic or normocalcemic PHPT or goiter. At baseline, cerebrovascular function (dynamic cerebral autoregulation and vasomotor reactivity) by transcranial Doppler and neuropsychological function were compared between all three groups. A subset underwent parathyroidectomy or thyroidectomy, and was compared 6 months post-operatively. RESULTS: Mean cerebrovascular and neuropsychological function was normal and no worse in PHPT compared to controls preoperatively. Higher PTH was associated with worse intracerebral autoregulation (r = - 0.43, p = 0.02) and worse cognitive performance on some tests. Post-parathyroidectomy, mood improved significantly, but changes did not differ compared to those having thyroidectomy (p = 0.84). There was no consistent improvement in cognition or change in vascular function in either surgical group. CONCLUSIONS: Although higher PTH was associated with worse intracerebral autoregulation, cerebrovascular function, cognition and mood were normal in mild PHPT. PTX did not improve vascular or cognitive function. The observed improvement in mood cannot be clearly attributed to PTX. Notwithstanding the small sample size, the results do not support changing current criteria for parathyroidectomy to include cognitive complaints. However, the associations between PTH, cognition and cerebral autoregulation merit future studies in those with more severe hyperparathyroidism.

Disrupted radial and tibial microarchitecture in patients with monoclonal gammopathy of undetermined significance.

Patients with monoclonal gammopathy of undetermined significance (MGUS) had abnormalities in volumetric BMD (vBMD), microarchitecture, and stiffness at both the radius and tibia by high-resolution peripheral quantitative CT compared to matched controls. This is the first report demonstrating that patients with MGUS have microarchitectural deficits at multiple skeletal sites. INTRODUCTION: Fracture risk is elevated in patients with monoclonal gammopathy of undetermined significance (MGUS). However, the pathogenesis of bone disease in these patients is poorly understood. Prior work using high-resolution peripheral CT (HRpQCT) demonstrated abnormal microarchitecture at the radius, with predominantly cortical abnormalities. We hypothesized that patients with MGUS have abnormal microarchitecture at both radius and tibia compared to controls, reflecting global skeletal effects of the disease. METHODS: This case-control study enrolled 36 subjects; patients with MGUS (n = 12) were matched 1:2 by age, sex, and race to controls (n = 24). Areal BMD (aBMD) was measured by DXA, vBMD, and microarchitecture by HRpQCT, and whole bone stiffness by finite element analysis. Serum was drawn for markers of bone metabolism and inflammation. RESULTS: By DXA, MGUS patients had lower aBMD at the lumbar spine, femoral neck, and 1/3 radius. Markers of bone metabolism and inflammation did not differ. By HRpQCT at the radius, MGUS patients had lower total, trabecular and cortical density, lower trabecular number, and greater trabecular separation and heterogeneity. At the tibia, MGUS patients had lower total and trabecular density, lower trabecular number, greater separation and heterogeneity, and lower whole bone stiffness. CONCLUSIONS: Patients with MGUS had lower vBMD, cortical, and trabecular abnormalities at the radius compared to matched controls. At the tibia, trabecular abnormalities predominated. These results suggest that in addition to previously described cortical deficits, deterioration of trabecular bone may contribute to a generalized skeletal fragility in patients with MGUS.

Abnormal microarchitecture and stiffness in postmenopausal women using chronic inhaled glucocorticoids.

Postmenopausal (PM) women using inhaled glucocorticoids (IGCs) had substantial abnormalities in volumetric BMD (vBMD), microarchitecture, and stiffness using high resolution peripheral computed tomography (HRpQCT) compared to age- and race-matched controls. Abnormalities were most severe at the radius. These preliminary results suggest that there may be major, heretofore unrecognized, skeletal deficits in PM women using IGCs. INTRODUCTION: While oral glucocorticoids are well recognized to have destructive skeletal effects, less is known about the effects of IGCs. The detrimental skeletal effects of IGCs may be greatest in PM women, in whom they compound negative effects of estrogen loss and aging. The goal of this study was to evaluate microarchitecture and stiffness in PM women using chronic IGCs. METHODS: This case-control study compared PM women using IGCs for ≥ 6 months (n = 20) and controls matched for age and race/ethnicity (n = 60). Skeletal parameters assessed included areal BMD (aBMD) by DXA, trabecular and cortical vBMD and microarchitecture by HRpQCT of the radius and tibia, and whole bone stiffness by finite element analysis. RESULTS: By DXA, mean values in both groups were in the osteopenic range; hip aBMD was lower in IGC users (P < 0.04). By HRpQCT, IGC users had lower total, cortical, and trabecular vBMD at both radius and tibia (all P < 0.05). IGC users had lower cortical thickness, lower trabecular number, greater trabecular separation and heterogeneity at the radius (all P < 0.03), and greater heterogeneity at the tibia (P < 0.04). Whole bone stiffness was lower in IGC users at radius (P < 0.03) and tended to be lower at the tibia (P = 0.09). CONCLUSIONS: PM women using IGCs had substantial abnormalities in vBMD, microarchitecture, and stiffness compared to controls. These abnormalities were most severe at the radius. These preliminary results suggest that there may be major, heretofore unrecognized, skeletal deficits in PM women using IGCs.

Bone density and microarchitecture in hepatitis C and HIV-coinfected postmenopausal minority women.

We found that HIV+/HCV+ women had 7-8% lower areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry (DXA) at the spine, hip, and radius (p < 0.01) and 5-7% lower volumetric BMD (vBMD) by central quantitative computed tomography (cQCT) at the spine and hip (p < 0.05). These data suggest that true deficits in vBMD may contribute to bone fragility and excess fractures reported in HIV+/HCV+ women. INTRODUCTION: aBMD by DXA is lower in persons coinfected with HIV and HCV (HIV+/HCV+) than with HIV monoinfection (HIV+). However, weight is often also lower with HCV infection, and measurement of aBMD by DXA can be confounded by adiposity; we aimed to determine whether true vBMD is also lower in HIV+/HCV+ coinfection. METHODS: We measured aBMD of the lumbar spine (LS), total hip (TH), femoral neck (FN), and ultradistal radius (UDR) by DXA and vBMD of the spine and hip by cQCT and of the distal radius and tibia by high-resolution peripheral QCT (HRpQCT) in 37 HIV+/HCV+ and 119 HIV+ postmenopausal women. Groups were compared using Student's t tests with covariate adjustment by multiple regression analysis. RESULTS: HIV+/HCV+ and HIV+ women were of similar age and race/ethnicity. HIV+/HCV+ women had lower body mass index (BMI) and trunk fat and were more likely to smoke and less likely to have a history of AIDS. In HIV+/HCV+ women, aBMD by DXA was 7-8% lower at the LS, TH, and UDR (p < 0.01). Similarly, vBMD by cQCT was 5-7% lower at the LS and TH (p < 0.05). Between-group differences in LS aBMD and vBMD remained significant after adjustment for BMI, smoking, and AIDS history. Tibial total vBMD by HRpQCT was 10% lower in HIV+/HCV+ women. CONCLUSION: HIV+/HCV+ postmenopausal women had significantly lower spine aBMD and vBMD. These deficits in vBMD may contribute to bone fragility and excess fractures reported in HIV+/HCV+ women.

Frailty in Postmenopausal African American and Hispanic HIV-Infected Women.

Studies suggest frailty occurs earlier in HIV-infected individuals, but data in postmenopausal HIV-infected women are lacking. We assessed the prevalence of frailty and association with anthropometric measures in HIV-infected and uninfected postmenopausal women. Fried's frailty phenotype was measured in HIV-infected and uninfected Hispanic and African American postmenopausal women participating in a study of bone metabolism; fat and lean mass were measured by whole body dual energy x-ray absorptiometry (DXA). Multivariable logistic regression evaluated frailty risk factors. The study was conducted at Columbia University Medical Center between 2002 and 2007. The participants were 61 HIV-infected and 27 uninfected Hispanic and African American postmenopausal women. The study compared prevalence and predictors of frailty in HIV-infected and uninfected postmenopausal women. Prevalence of frailty tended to be higher among HIV-infected than uninfected controls (11.5% vs 0% p=0.07). Surprisingly, among HIV-infected women, total body fat, not lean mass, was associated with frailty in multivariate analysis. Higher prevalence of frailty in African American and Hispanic HIV-infected postmenopausal women (11.5%) was similar to the 11% prevalence reported in minority women who were 10 years older in the general population. Our data suggest that frailty occurs earlier in HIV-infected postmenopausal women, but larger longitudinal studies are necessary to confirm whether musculoskeletal aging is accelerated by HIV infection.

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.

UNLABELLED: Measurement 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. INTRODUCTION: Excess 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 ((1)H-MRS). In this study, we evaluate relationships between marrow fat assessed using both methods in the same subjects for the first time. METHODS: Sixteen 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 (1)H-MRS. RESULTS: At L3, fat fraction by (1)H-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. CONCLUSIONS: In summary, measurement of marrow fat in transiliac crest biopsies correlates with marrow fat at the spine but not the proximal femur by (1)H-MRS. There were site-specific differences in marrow fat quantity and in the relationships between marrow fat and bone volume.