Are Nonalcoholic Fatty Liver Disease and Bone Mineral Density Associated? - A Cross-Sectional Study Using Liver Biopsy and Dual-Energy X-Ray Absorptiometry.

There is controversy regarding the association between nonalcoholic fatty liver disease (NAFLD) and osteoporosis. Our study aim was to assess bone mineral density (BMD) in patients with biopsy-proven NAFLD and examine if the severity of NAFLD affects BMD. A total of 147 adult women (n = 108) and men (n = 39) aged 18-76 years (mean ± standard deviation [SD] age 45.3 ± 12.5) were recruited in this cross-sectional study and underwent a liver biopsy and dual-energy X-ray absorptiometry (DXA). NAFLD activity score (NAS) based on the degree of steatosis, lobular inflammation and hepatocellular ballooning was used to assess NAFLD severity. The majority of subjects, 53%, had steatosis, 25% had nonalcoholic steatohepatitis (NASH) whereas 23% served as control subjects with no evidence of NAFLD. There were no significant differences in the lumbar spine (1.09 ± 0.12, 1.11 ± 0.18, and 1.12 ± 0.15 g/cm2, p = 0.69, in controls, steatosis, and NASH, respectively) or hip BMD (1.10 ± 0.15, 1.12 ± 0.13, and 1.09 ± 0.13 g/cm2, p = 0.48, in controls, steatosis, and NASH, respectively) between the groups. Adjusting for age, gender, body mass index, and diabetes in multiple regression models did not alter the results. There was no correlation between NAS and neither lumbar spine BMD (r = 0.06, p = 0.471), nor hip BMD (r = -0.03, p = 0.716). In conclusion, BMD was similar across the spectrum of NAFLD in both genders and not related to the severity of the underlying histological lesions, suggesting that neither steatosis nor NASH exerts a detrimental effect on BMD in these relatively young patients. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Elevated Bone Remodeling Markers of CTX and P1NP in Addition to Sclerostin in Patients with X-linked Hypophosphatemia: A Cross-Sectional Controlled Study.

Aspects of bone remodeling have only been scarcely studied in X-linked hypophosphatemia (XLH). In this cross-sectional controlled study, we assessed biochemical indices of bone remodeling and sclerostin in 27 adult patients (median age 47 [range 24-79] years, 19 women, 8 men) with XLH matched with 81 healthy control subjects (1:3) with respect to age-, sex-, and menopausal status. Markers of bone resorption (carboxyterminal cross-linked telopeptide of type 1 collagen, CTX) and formation (N-terminal propeptide of type 1 procollagen, P1NP) were higher in XLH patients compared to controls (median [IQR] 810 [500-1340] vs 485 [265-715] ng/l and 90 [57-136] vs 49 [39-65] ug/l, respectively, both p < 0.001) as well as sclerostin (0.81 [0.60-1.18] vs 0.54 [0.45-0.69] ng/ml, p < 0.001). Similar differences were found when comparing currently treated (with phosphate and alfacalcidol) (n = 11) and untreated (n = 16) XLH patients with their respective controls. We found no significant associations with treatment status and indices of bone remodeling or sclerostin although sclerostin tended to be increased in untreated versus treated (p = 0.06). In contrast to previous histomorphometric studies suggesting a low remodeling activity in XLH, these biochemical indices suggest high osteoblast and osteoclast activity. Further studies are needed to ascertain if the higher sclerostin level in XLH is related to osteocyte dysfunction or represents a secondary phenomenon.

Bone disease in diabetes: another manifestation of microvascular disease?

Type 1 and type 2 diabetes are generally accepted to be associated with increased bone fracture risk. However, the pathophysiological mechanisms of diabetic bone disease are poorly understood, and whether the associated increased skeletal fragility is a comorbidity or a complication of diabetes remains under debate. Although there is some indication of a direct deleterious effect of microangiopathy on bone, the evidence is open to question, and whether diabetic osteopathy can be classified as a chronic, microvascular complication of diabetes remains uncertain. Here, we review the current knowledge of potential contributory factors to diabetic bone disease, particularly the association between diabetic microangiopathy and bone mineral density, bone structure, and bone turnover. Additionally, we discuss and propose a pathophysiological model of the effects of diabetic microvascular disease on bone, and examine the progression of bone disease alongside the evolution of diabetes.

Bone structural changes after gastric bypass surgery evaluated by HR-pQCT: a two-year longitudinal study.

OBJECTIVE, DESIGN AND METHODS: Roux-en-Y gastric bypass (RYGB) has proved successful in attaining sustained weight loss but may lead to metabolic bone disease. To assess impact on bone mass and structure, we measured a real bone mineral density at the hip and spine by dual-energy X-ray absorptiometry, and volumetric BMD (vBMD) and bone microarchitecture at the distal radius and tibia by high-resolution peripheral quantitative CT in 25 morbidly obese subjects (15 females, 10 males) at 0, 12 and 24 months after RYGB. Bone turnover markers (BTMs), calciotropic and gut hormones and adipokines were measured at the same time points. RESULTS: After a 24.1% mean weight loss from baseline to month 12 (P < 0.001), body weight plateaued from month 12 to 24 (-0.9%, P = 0.50). However, cortical and trabecular vBMD and microarchitecture deteriorated through the 24 months, such that there was a 5 and 7% reduction in estimated bone strength at the radius and tibia respectively (both P < 0.001). The declines observed in the first 12 months were matched or exceeded by declines in the 12- to 24-month period. While a significant increase in BTMs and decrease in leptin and insulin were seen at 24 months, these changes were maximal at month 12 and stabilized from month 12 to 24. CONCLUSIONS: Despite weight stabilization and maintenance of metabolic parameters, bone loss and deterioration in bone strength continued and were substantial in the second year. The clinical importance of these changes in terms of increased risk of developing osteoporosis and fragility fractures remain an important concern.

Association Between Insulin Resistance and Bone Structure in Nondiabetic Postmenopausal Women.

CONTEXT: The clinical consequences of insulin resistance and hyperinsulinemia on bone remain largely unknown. OBJECTIVE: The objective of the study was to evaluate the effect of insulin resistance on peripheral bone geometry, volumetric bone mineral density (vBMD), bone microarchitecture, and estimated bone strength. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study included 146 postmenopausal, nondiabetic Caucasian women (mean age 60.3 ± 2.7 y) who were participating in the Study of Women's Health Across the Nation. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: High-resolution peripheral quantitative computed tomography was used to assess bone density and microstructure at the distal radius and tibia. Fasting insulin and glucose were measured and insulin resistance was estimated using homeostasis model assessment of insulin resistance (HOMA-IR), with higher values indicating greater insulin resistance. RESULTS: There was a negative association between HOMA-IR and bone size and a positive association between HOMA-IR and total vBMD, trabecular vBMD, trabecular thickness, and cortical thickness at the radius and tibia. These relationships remained, even after adjusting for body weight and other potential covariates (eg, time since menopause, cigarette smoking, physical activity, prior use of osteoporosis medications or glucocorticoids). CONCLUSIONS: In nondiabetic, postmenopausal women, insulin resistance was associated with smaller bone size, greater volumetric bone mineral density, and generally favorable bone microarchitecture at weight-bearing and nonweight-bearing skeletal sites. These associations were independent of body weight and other potential covariates, suggesting that hyperinsulinemia directly affects bone structure independent of obesity and may explain, in part, the higher trabecular bone density and favorable trabecular microarchitecture seen in individuals with type 2 diabetes mellitus.

Age- and Sex-Related Changes in Bone Microarchitecture and Estimated Strength: A Three-Year Prospective Study Using HRpQCT.

Although projections from cross-sectional studies have shown that bone loss leading to osteoporosis begins around menopause in women and later in life in men, this has not been examined longitudinally in population-based studies using high-resolution technology capable of distinguishing cortical (Ct) and trabecular (Tb) bone microarchitecture. The aim of this 3-year prospective study was to investigate age- and sex-related changes in bone compartment-specific geometry, volumetric bone mineral density (vBMD), microarchitecture, and estimated strength. The distal radius and tibia were imaged at baseline and after 3 years (median 3.0; range, 2.7 to 3.9 years) using high-resolution peripheral computed tomography (HRpCT) in an age- and sex-stratified, population-based, random sample of white men and women (n = 260) aged 21 to 82 years. In general, at the radius and tibia there was a moderate annual increase in cortical thickness (Ct.Th) that seemed to offset the increase in cortical porosity (Ct.Po), resulting in net annual increase in cortical vBMD (Ct.vBMD) in premenopausal women and young men. With advancing age, postmenopausal women displayed significant bone loss with decreased trabecular vBMD (Tb.vBMD) (due to loss of entire trabeculae) and Ct.vBMD (manifested as increase in Ct.Po and decrease in Ct.Th) at the radius, and a decline in Ct.vBMD (with increasing Ct.Po) at the tibia, resulting in loss of estimated bone strength. In contrast, men had a lower rate of bone loss with advancing age with smaller increases in Ct.Po at both the skeletal sites. In summary, the pattern of bone loss in men and women was discrepant, with women losing more bone than men with aging, although with a dominance of cortical over trabecular bone loss at the peripheral sites in both sexes. This conforms to epidemiological evidence that most fractures occurring in old age are predominantly at cortical peripheral sites, with women having a higher incidence of fractures than men at any given age. © 2016 American Society for Bone and Mineral Research.

Type 2 diabetes and the skeleton: new insights into sweet bones.

Substantial evidence shows that skeletal fragility should be considered among the complications associated with type 2 diabetes. Individuals with type 2 diabetes have increased fracture risk, despite normal bone mineral density (BMD) and high BMI-factors that are generally protective against fractures. The mechanisms underlying skeletal fragility in diabetes are not completely understood, but are multifactorial and likely include effects of obesity, hyperglycaemia, oxidative stress, and accumulation of advanced glycation end products, leading to altered bone metabolism, structure, and strength. Clinicians should be aware that BMD measurements underestimate fracture risk in people with type 2 diabetes, and that new treatments for diabetes, with neutral or positive effects on skeletal health, might play a part in the management of diabetes in those at high risk of fracture. Data for the optimum management of osteoporosis in patients with type 2 diabetes are scarce, but in the absence of evidence to the contrary, physicians should follow guidelines established for postmenopausal osteoporosis.

Compromised cortical bone compartment in type 2 diabetes mellitus patients with microvascular disease.

OBJECTIVE AND DESIGN: Patients with type 2 diabetes mellitus (T2D) have an increased fracture risk despite a normal or elevated bone mineral density (BMD). The aim of this cross-sectional in vivo study was to assess parameters of peripheral bone microarchitecture, estimated bone strength and bone remodeling in T2D patients with and without diabetic microvascular disease (MVD+ and MVD- respectively) and to compare them with healthy controls. METHODS: Fifty-one T2D patients (MVD+ group: n=25) were recruited from Funen Diabetic Database and matched for age, sex and height with 51 healthy subjects. High-resolution peripheral quantitative tomography (HR-pQCT) was used to assess bone structure at the non-dominant distal radius and tibia. Estimated bone strength was calculated using finite element analysis. Biochemical markers of bone turnover were measured in all participants. RESULTS: After adjusting for BMI, MVD+ patients displayed lower cortical volumetric BMD (P=0.02) and cortical thickness (P=0.02) and higher cortical porosity at the radius (P=0.02) and a trend towards higher cortical porosity at the tibia (P=0.07) compared to controls. HR-pQCT parameters did not differ between MVD- and control subjects. Biochemical markers of bone turnover were significantly lower in MVD+ and MVD- patients compared to controls (all P<0.01). These were no significant correlations between disease duration, glycemic control (average glycated hemoglobin over the previous 3 years) and HR-pQCT parameters. CONCLUSION: Cortical bone deficits are not a characteristic of all T2D patients but of a subgroup characterized by the presence of microvascular complications. Whether this influences fracture rates in these patients needs further investigation.

Bone Geometry, Volumetric Density, Microarchitecture, and Estimated Bone Strength Assessed by HR-pQCT in Adult Patients With Type 1 Diabetes Mellitus.

The primary goal of this cross-sectional in vivo study was to assess peripheral bone microarchitecture, bone strength, and bone remodeling in adult type 1 diabetes (T1D) patients with and without diabetic microvascular disease (MVD+ and MVD-, respectively) and to compare them with age-, gender-, and height-matched healthy control subjects (CoMVD+ and CoMVD-, respectively). The secondary goal was to assess differences in MVD- and MVD+ patients. Fifty-five patients with T1DM (MVD+ group: n = 29) were recruited from the Funen Diabetes Database. Dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT) of the ultradistal radius and tibia, and biochemical markers of bone turnover were performed in all participants. There were no significant differences in HR-pQCT parameters between MVD- and CoMVD- subjects. In contrast, MVD+ patients had larger total and trabecular bone areas (p = 0.04 and p = 0.02, respectively), lower total, trabecular, and cortical volumetric bone mineral density (vBMD) (p < 0.01, p < 0.04, and p < 0.02, respectively), and thinner cortex (p = 0.03) at the radius, and lower total and trabecular vBMD (p = 0.01 and p = 0.02, respectively) at the tibia in comparison to CoMVD+. MVD+ patients also exhibited lower total and trabecular vBMD (radius p = 0.01, tibia p < 0.01), trabecular thickness (radius p = 0.01), estimated bone strength, and greater trabecular separation (radius p = 0.01, tibia p < 0.01) and network inhomogeneity (radius p = 0.01, tibia p < 0.01) in comparison to MVD- patients. These differences remained significant after adjustment for age, body mass index, gender, disease duration, and glycemic control (average glycated hemoglobin over the previous 3 years). Although biochemical markers of bone turnover were significantly lower in MVD+ and MVD- groups in comparison to controls, they were similar between the MVD+ and MVD- groups. The results of our study suggest that the presence of MVD was associated with deficits in cortical and trabecular bone vBMD and microarchitecture that could partly explain the excess skeletal fragility observed in these patients.