Chiyuan A. Zhang

Rapid cortical bone loss in patients with chronic kidney disease.

Chronic kidney disease (CKD) patients may have high rates of bone loss and fractures, but microarchitectural and biochemical mechanisms of bone loss in CKD patients have not been fully described. In this longitudinal study of 53 patients with CKD Stages 2 to 5D, we used dual‐energy X‐ray absorptiometry (DXA), high‐resolution peripheral quantitative computed tomography (HRpQCT), and biochemical markers of bone metabolism to elucidate effects of CKD on the skeleton. Median follow‐up was 1.5 years (range 0.9 to 4.3 years); bone changes were annualized and compared with baseline. By DXA, there were significant declines in areal bone mineral density (BMD) of the total hip and ultradistal radius: −1.3% (95% confidence interval [CI] −2.1 to −0.6) and −2.4% (95% CI −4.0 to −0.9), respectively. By HRpQCT at the distal radius, there were significant declines in cortical area, density, and thickness and increases in porosity: −2.9% (95% CI −3.7 to −2.2), −1.3% (95% CI −1.6 to −0.6), −2.8% (95% CI −3.6 to −1.9), and +4.2% (95% CI 2.0 to 6.4), respectively. Radius trabecular area increased significantly: +0.4% (95% CI 0.2 to 0.6), without significant changes in trabecular density or microarchitecture. Elevated time‐averaged levels of parathyroid hormone (PTH) and bone turnover markers predicted cortical deterioration. Higher levels of serum 25‐hydroxyvitamin D predicted decreases in trabecular network heterogeneity. These data suggest that significant cortical loss occurs with CKD, which is mediated by hyperparathyroidism and elevated turnover. Future investigations are required to determine whether these cortical losses can be attenuated by treatments that reduce PTH levels and remodeling rates.

Individual trabecula segmentation (ITS)-based morphological analyses and microfinite element analysis of HR-pQCT images discriminate postmenopausal fragility fractures independent of DXA measurements.

Osteoporosis is typically diagnosed by dual‐energy X‐ray absorptiometry (DXA) measurements of areal bone mineral density (aBMD). Emerging technologies, such as high‐resolution peripheral quantitative computed tomography (HR‐pQCT), may increase the diagnostic accuracy of DXA and enhance our mechanistic understanding of decreased bone strength in osteoporosis. Women with (nu2009=u200968) and without (nu2009=u2009101) a history of postmenopausal fragility fracture had aBMD measured by DXA, trabecular plate and rod microarchitecture measured by HR‐pQCT image‐based individual trabecula segmentation (ITS) analysis, and whole bone and trabecular bone stiffness by microfinite element analysis (µFEA) of HR‐pQCT images at the radius and tibia. DXA T‐scores were similar in women with and without fractures at the spine, hip, and 1/3 radius, but lower in fracture subjects at the ultradistal radius. Trabecular microarchitecture of fracture subjects was characterized by preferential reductions in trabecular plate bone volume, number, and connectivity over rod trabecular parameters, loss of axially aligned trabeculae, and a more rod‐like trabecular network. In addition, decreased thickness and size of trabecular plates were observed at the tibia. The differences between groups were greater at the radius than the tibia for plate number, rod bone volume fraction and number, and plate–rod and rod–rod junction densities. Most differences between groups remained after adjustment for T‐score by DXA. At a fixed bone volume fraction, trabecular plate volume, number, and connectivity were directly associated with bone stiffness. In contrast, rod volume, number, and connectivity were inversely associated with bone stiffness. In summary, HR‐pQCT‐based ITS and µFEA measurements discriminate fracture status in postmenopausal women independent of DXA measurements. Moreover, these results suggest that preferential loss of plate‐like trabeculae contribute to lower trabecular bone and whole bone stiffness in women with fractures. We conclude that HR‐pQCT‐based ITS and µFEA measurements increase our understanding of the microstructural pathogenesis of fragility fracture in postmenopausal women.

Cardiac Structure and Diastolic Function in Mild Primary Hyperparathyroidism

CONTEXTnData on the presence, extent, and reversibility of cardiovascular disease in primary hyperparathyroidism (PHPT) are conflicting.nnnOBJECTIVEnTo evaluate the heart in PHPT, we assessed cardiac structure and diastolic function in patients with mild PHPT compared with age- and sex-matched controls.nnnDESIGNnThis was a case-control study.nnnSETTINGSnThe study was conducted in a university hospital Metabolic Bone Diseases Unit.nnnPARTICIPANTSnFifty-four men and women with PHPT and 76 controls without PHPT participated in the study.nnnOUTCOME MEASURESnWe measured left ventricular mass index (LVMI), the presence of mitral annular calcification, the ratio of early to late diastolic mitral inflow velocities (E/A), and early diastolic velocity of the lateral mitral annulus using Doppler tissue imaging (tissue Doppler e).nnnRESULTSnPatients had mild disease with mean (+/-sd) serum calcium 10.5 +/- 0.5 mg/dl and PTH 96 +/- 45 pg/ml. LVMI and diastolic function were normal in PHPT. There was no difference in LVMI (98 +/- 23 vs. 96 +/- 24 g/m(2), P = 0.69) or the frequency of mitral annular calcification between PHPT cases and controls. Diastolic function variables (E/A and tissue Doppler e) were higher (better) in cases compared with controls, although both were within the reference range. PHPT patients with low E/A had higher serum PTH (121 +/- 36 vs. 89 +/- 46 pg/ml, P = 0.03) and calcium (10.8 +/- 0.4 vs. 10.5 +/- 0.5 mg/dl, P = 0.05) than those with normal values. Finally, we found LVMI to be inversely associated with serum 25-hydroxyvitamin D in PHPT (r = -0.29, P < 0.05). All findings persisted after adjustment for group differences in cardiovascular risk factors.nnnCONCLUSIONSnPatients with biochemically mild PHPT do not have evidence of increased left ventricular mass, diastolic dysfunction, or increased valvular calcifications. However, the data support an association between low vitamin D levels and the development of left ventricular hypertrophy in this disorder. Finally, the increased serum calcium and PTH levels in those with diastolic dysfunction suggest that disease severity may determine the presence of cardiac manifestations in PHPT.

Low Bone Mass and High Bone Turnover in Postmenopausal Human Immunodeficiency Virus-Infected Women

CONTEXTnLow bone mineral density (BMD) is commonly reported in young men and women with HIV infection, and fracture rates may be higher. With effective antiretroviral therapy (ART), the HIV population is aging. However, little is known about the skeletal status of postmenopausal women.nnnOBJECTIVEnWe aimed to assess the effects of HIV infection and ART on BMD and bone turnover in postmenopausal minority women.nnnDESIGN, SETTING, AND PATIENTSnA prospective cohort study was performed in 92 HIV+ and 95 HIV- postmenopausal Hispanic and African-American women.nnnMAIN OUTCOME MEASURESnWe measured BMD by dual-energy x-ray absorptiometry, fracture prevalence, serum levels of inflammatory cytokines (TNFalpha, IL-6), bone turnover markers, calciotropic hormones, and estrone.nnnRESULTSnHIV+ women were younger (56 +/- 1 vs. 60 +/- 1 yr; P < 0.01) and had lower BMI (28 +/- 1 vs. 30 +/- 1 kg/m(2); P < 0.01) and estrone levels. Prevalence of T scores below -1.0 was greater in HIV+ women at the spine (78 vs. 64%; P < 0.05), total hip (45 vs. 29%; P < 0.05), and femoral neck (64 vs. 46%; P < 0.05), and Z scores adjusted for BMI were lower in HIV+ women at the same sites. Serum TNFalpha, N-telopeptide, and C-telopeptide were significantly higher in HIV+ than HIV- women, particularly those receiving ART. HIV+ status was independently and negatively associated with spine and hip BMD after adjustment for age, ethnicity, BMI, and alcohol.nnnCONCLUSIONnThe lower BMD, higher prevalence of low BMD, and higher levels of bone turnover markers detected in HIV+ postmenopausal minority women could place them at high risk for future fractures.

Higher Rates of Bone Loss in Postmenopausal HIV-Infected Women: A Longitudinal Study

CONTEXT AND OBJECTIVEnThe objective of the study was to assess the effects of HIV infection and antiretroviral therapy on change in bone mineral density (BMD) in postmenopausal minority women.nnnDESIGN, SETTING, AND PATIENTSnWe report a longitudinal analysis of change in BMD with a median duration of 15.4 (interquartile range 13.1, 20.7) months in a prospective cohort study of 128 (73 HIV+, 55 HIV-) postmenopausal Hispanic and African-American women.nnnMAIN OUTCOME MEASURESnAnnualized change in BMD by dual-energy x-ray absorptiometry and correlation with baseline markers of bone turnover and serum levels of inflammatory cytokines were measured.nnnRESULTSnHIV+ women were younger (56 ± 1 vs. 59 ± 1 yr, P < 0.05) and had lower body mass index (BMI; 28 ± 1 vs. 31 ± 1 kg/m(2), P < 0.01). The majority of HIV+ women were on established antiretroviral therapy for more than 3 yr. At baseline, BMD, adjusted for age, race, and BMI, was lower in HIV+ women at the lumbar spine (LS), total hip, and radius and serum C-telopeptide was higher. Annualized rates of bone loss adjusted for baseline BMD were higher in HIV+ women by 2.4-fold at the LS (-1.2 ± 0.3% vs. -0.5 ± 0.3%, P = 0.0009), 3.7-fold at the one third radius (-1.1 ± 0.2% vs. -0.3 ± 0.2, P = 0.006) and 1.7-fold at the ultradistal radius (-1.2 ± 0.2% vs. -0.7 ± 0.2%, P = 0.02). In multivariate analysis, HIV+ status predicted bone loss at the LS, total hip, and ultradistal radius. Among HIV+ women, lower BMI, higher markers of bone turnover levels, and tenofovir were associated with more bone loss.nnnCONCLUSIONnHIV+ postmenopausal minority women had lower BMD, increased bone turnover, and higher rates of bone loss than HIV- women. These features may place these women at increased risk for fracture as they age.

Vitamin D deficiency in HIV-infected postmenopausal Hispanic and African-American women

SummaryWe evaluated vitamin D status in HIV+ and HIV− postmenopausal African-American (AA) and Hispanic women. Most women (74-78%) had insufficient 25-hydroxyvitamin D (25OHD) levels, regardless of HIV status. 25OHD was lower in AA women and women lacking supplement use, providing support for screening and supplementation. Among HIV+ women, 25OHD was associated with current CD4 but not type of antiretroviral therapy.IntroductionTo evaluate vitamin D status and factors associated with vitamin D deficiency and insufficiency in HIV-infected (HIV+) postmenopausal minority women.MethodsIn this cross-sectional study, 89 HIV+ and 95 HIV− postmenopausal women (33% AA and 67% Hispanic) underwent assessment of 25OHD, 1,25-dihydroxyvitamin D, parathyroid hormone, markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry.ResultsThe prevalence of low 25OHD did not differ by HIV status; the majority of both HIV+ and HIV− women (74-78%) had insufficient levels (<30xa0ng/ml). Regardless of HIV status, 25OHD was significantly lower in AA subjects, and higher in subjects who used both calcium and multivitamins. In HIV+ women on antiretroviral therapy (ART), 25OHD was directly associated with current CD4 count (ru2009=u20090.32; pu2009<u20090.01) independent of age, ethnicity, BMI, or history of AIDS-defining illness. No association was observed between 1,25(OH)2D and CD4 count or between serum 25OHD, 1,25(OH)2D or PTH and type of ART.ConclusionsIn postmenopausal minority women, vitamin D deficiency was highly prevalent and associated with AA race and lack of supplement use, as well as lower current CD4 cell count. These results provide support for screening and repletion of vitamin D in HIV+ patients.

Lower peak bone mass and abnormal trabecular and cortical microarchitecture in young men infected with HIV early in life.

Introduction:HIV infection and antiretroviral therapy (ART) early in life may interfere with acquisition of peak bone mass, thereby increasing fracture risk in adulthood. Methods:We conducted a cross-sectional study of dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) in 30 HIV-infected African–American or Hispanic Tanner stage 5 men aged 20–25 on ART (15 perinatally infected and 15 infected during adolescence) and 15 HIV-uninfected controls. Results:HIV-infected men were similar in age and BMI, but were more likely to be African–American (Pu200a=u200a0.01) than uninfected men. DXA-derived areal bone mineral density (aBMD) Z-scores were 0.4–1.2 lower in HIV-infected men at the spine, hip, and radius (all Pu200a<u200a0.05). At the radius and tibia, total and trabecular volumetric BMD (vBMD), and cortical and trabecular thickness were between 6 and 19% lower in HIV-infected than uninfected men (Pu200a<0.05). HIV-infected men had dramatic deficiencies in plate-related parameters by individual trabeculae segmentation (ITS) analyses and 14–17% lower bone stiffness by finite element analysis. Differences in most HR-pQCT parameters remained significant after adjustment for race/ethnicity. No DXA or HR-pQCT parameters differed between men infected perinatally or during adolescence. Conclusion:At an age by which young men have typically acquired peak bone mass, HIV-infected men on ART have lower BMD, markedly abnormal trabecular plate and cortical microarchitecture, and decreased whole bone stiffness, whether infected perinatally or during adolescence. Reduced bone strength in young adults infected with HIV early in life may place them at higher risk for fractures as they age.

Microarchitecture and Peripheral BMD are Impaired in Postmenopausal White Women With Fracture Independently of Total Hip T‐Score: An International Multicenter Study

Because single‐center studies have reported conflicting associations between microarchitecture and fracture prevalence, we included high‐resolution peripheral quantitative computed tomography (HR‐pQCT) data from five centers worldwide into a large multicenter analysis of postmenopausal women with and without fracture. Volumetric BMD (vBMD) and microarchitecture were assessed at the distal radius and tibia in 1379 white postmenopausal women (age 67u2009±u20098 years); 470 (34%) had at least one fracture including 349 with a major fragility fracture. Age, height, weight, and total hip T‐score differed across centers and were employed as covariates in analyses. Women with fracture had higher BMI, were older, and had lower total hip T‐score, but lumbar spine T‐score was similar between groups. At the radius, total and trabecular vBMD and cortical thickness were significantly lower in fractured women in three out of five centers, and trabecular number in two centers. Similar results were found at the tibia. When data from five centers were combined, however, women with fracture had significantly lower total, trabecular, and cortical vBMD (2% to 7%), lower trabecular number (4% to 5%), and thinner cortices (5% to 6%) than women without fracture after adjustment for covariates. Results were similar at the radius and tibia. Similar results were observed with analysis restricted to major fragility fracture, vertebral and hip fractures, and peripheral fracture (at the radius). When focusing on osteopenic women, each SD decrease of total and trabecular vBMD was associated with a significantly increased risk of major fragility fracture (ORu2009=u20091.55 to 1.88, p < 0.01) after adjustment for covariates. Moreover, trabecular architecture modestly improved fracture discrimination beyond peripheral total vBMD. In conclusion, we observed differences by center in the magnitude of fracture/nonfracture differences at both the distal radius and tibia. However, when data were pooled across centers and the sample size increased, we observed significant and consistent deficits in vBMD and microarchitecture independent of total hip T‐score in all postmenopausal white women with fracture and in the subgroup of osteopenic women, compared to women who never had a fracture.

Effects of HIV infection and antiretroviral therapy with ritonavir on induction of osteoclast-like cells in postmenopausal women.

SummaryRitonavir (RTV) is a commonly used antiretroviral associated with bone loss. We show that peripheral blood mononuclear cells (PBMCs) from human immunodeficiency virus (HIV)-positive women on RTV are more likely to differentiate into osteoclast-like cells when cultured with their own sera than PBMCs and sera from HIV− women or HIV+ on other antiretrovirals.IntroductionRTV increases differentiation of human adherent PBMCs to functional osteoclasts in vitro, and antiretroviral regimens containing RTV have been associated with low bone mineral density (BMD) and bone loss.MethodsBMD, proresorptive cytokines, bone turnover markers (BTMs), and induction of osteoclast-like cells from adherent PBMCs incubated either with macrophage colony-stimulating factor (MCSF) and receptor activator of nuclear factor κB ligand (RANKL) or with autologous serum were compared in 51 HIV− and 68 HIV+ postmenopausal women.ResultsBMD was lower, and serum proresorptive cytokines and BTMs were higher in HIV+ versus HIV− women. Differentiation of osteoclast-like cells from adherent PBMCs exposed to either MCSF/RANKL or autologous serum was greater in HIV+ women. Induction of osteoclast-like cells was greater from PBMCs exposed to autologous sera from HIV+ women on RTV-containing versus other regimens (172u2009±u200914% versus 110u2009±u200910%, pu2009<u20090.001). Serum-based induction of osteoclast-like cells from adherent PBMCs correlated with certain BTMs but not BMD.ConclusionsHIV infection and antiretroviral therapy are associated with higher BTMs and increased differentiation of osteoclast-like cells from adherent PBMCs, especially in women on regimens containing RTV. HIV+ postmenopausal women receiving RTV may be at greater risk for bone loss.

Circulating Sclerostin Levels and Markers of Bone Turnover in Chinese-American and White Women

CONTEXTnChinese-American women have bone microarchitectural features that confer greater bone stiffness compared to white women, but the physiology underlying these findings has not been investigated.nnnOBJECTIVEnThe purpose of the study was to assess racial differences in serum sclerostin and bone turnover markers (BTMs), and to explore their associations with each other, volumetric bone mineral density (BMD), and bone microarchitecture in Chinese-American and white women.nnnDESIGN AND SETTINGnWe conducted a cross-sectional study at a university hospital.nnnPARTICIPANTSnWe studied 138 women.nnnRESULTSnSerum osteocalcin was 19-28% lower in pre- and postmenopausal Chinese-American vs white women, respectively (both P < .01). C-Terminal telopeptide of type I collagen (CTX) level was 18-22% lower in pre- and postmenopausal Chinese-American vs white women (both P < .05). Pre- vs postmenopausal differences in osteocalcin and CTX were greater in white vs Chinese-American women. Sclerostin levels were similar in both races, but BTMs were differentially associated with sclerostin by race and menopausal status. BTMs were not correlated with sclerostin in Chinese-Americans. CTX and bone-specific alkaline phosphatase were positively associated with sclerostin (r = 0.353, r = 0.458; both P < .05) in white premenopausal women. In contrast, in postmenopausal white women, the associations of sclerostin with amino-terminal propeptide of type I procollagen, isoform 5b of tartrate-resistant acid phosphatase, and CTX were negative (all P < .05). Adjusting for covariates, sclerostin was positively associated with areal BMD in both races.nnnCONCLUSIONSnLower BTMs in Chinese-American women and greater age-related differences in BTMs among white women provide a physiological framework to account for racial differences in BMD, microarchitecture, and fracture.