Are the High Hip Fracture Rates Among Norwegian Women Explained by Impaired Bone Material Properties?

Hip fracture rates in Norway rank among the highest in the world, more than double that of Spanish women. Previous studies were unable to demonstrate significant differences between the two populations with respect to bone mass or calcium metabolism. In order to test whether the difference in fracture propensity between both populations could be explained by differences in bone material quality we assessed bone material strength using microindentation in 42 Norwegian and 46 Spanish women with normal BMD values, without clinical or morphometric vertebral fractures, no clinical or laboratory signs of secondary osteoporosis, and without use of drugs with known influence on bone metabolism. Bone material properties were assessed by microindentation of the thick cortex of the mid tibia following local anesthesia of the area using the Osteoprobe device (Active Life Scientific, Santa Barbara, CA, USA). Indentation distance was standardized against a calibration phantom of methylmethacrylate and results, as percentage of this reference value, expressed as bone material strength index units (BMSi). We found that the bone material properties reflected in the BMSi value of Norwegian women was significantly inferior when compared to Spanish women (77 ± 7.1 versus 80.7 ± 7.8, p < 0.001). Total hip BMD was significantly higher in Norwegian women (1.218 g/cm² versus 0.938 g/cm², p < 0.001) but regression analysis revealed that indentation values did not vary with BMD r² = 0.03 or age r² = 0.04. In conclusion Norwegian women show impaired bone material properties, higher bone mass, and were taller than Spanish women. The increased height will increase the impact on bone after falls, and impaired bone material properties may further enhance the risk fracture after such falls. These ethnic differences in bone material properties may partly explain the higher propensity for fracture in Norwegian women. © 2015 American Society for Bone and Mineral Research.     

Type 2 Diabetes Mellitus Is Associated With Better Bone Microarchitecture But Lower Bone Material Strength and Poorer Physical Function in Elderly Women: A Population‐Based Study

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of fractures according to several studies. The underlying mechanisms remain unclear, although small case‐control studies indicate poor quality of the cortical bone. We have studied a population‐based sample of women aged 75 to 80 years in Gothenburg, randomly invited from the population register. Areal bone mineral density (aBMD) was measured by dual‐energy X‐ray absorptiometry (Hologic Discovery A), bone microarchitecture by high‐resolution peripheral quantitative computed tomography (HR‐pQCT; ExtremeCT from Scanco Medical AG), and reference point indentation was performed with Osteoprobe (Active Life Scientific). Women with T2DM (n = 99) had higher aBMD compared to controls (n = 954). Ultradistal tibial and radial trabecular bone volume fraction (+11% and +15%, respectively), distal cortical volumetric BMD (+1.6% and +1.7%), cortical area (+11.5% and +9.3%), and failure load (+7.7% and +12.9%) were higher in diabetics than in controls. Cortical porosity was lower (mean ± SD: 1.5% ± 1.1% versus 2.0% ± 1.7%, p = 0.001) in T2DM in the distal radius but not in the ultradistal radius or the tibia. Adjustment for covariates (age, body mass index, glucocorticoid treatment, smoking, physical activity, calcium intake, bone‐active drugs) eliminated the differences in aBMD but not in HR‐pQCT bone variables. However, bone material strength index (BMSi) by reference point indentation was lower in T2DM (74.6 ± 7.6 versus 78.2 ± 7.5, p < 0.01), also after adjustment, and women with T2DM performed clearly worse in measures of physical function (one leg standing: –26%, 30‐s chair‐stand test: –7%, timed up and go: +12%, walking speed: +8%; p < 0.05‐0.001) compared to controls. In conclusion, we observed a more favorable bone microarchitecture but no difference in adjusted aBMD in elderly women with T2DM in the population compared to nondiabetics. Reduced BMSi and impaired physical function may explain the increased fracture risk in T2DM. © 2016 American Society for Bone and Mineral Research.     

Impact Microindentation: Consistency of Serial Measurements and Alterations in Patients With Paget's Disease of the Tibia

Impact microindentation (IMI) is a new technique for the in vivo measurement of tissue‐level properties of cortical bone in humans. To address issues related to the proper application of IMI in clinical practice and to directly examine cortical bone properties in patients with tibia pathology, we studied 11 subjects without tibia pathology and nine patients with Paget's disease of the tibia in biochemical remission after bisphosphonate treatment. Serial indentations in the tibias of both legs were performed in all subjects by a single operator until 10 adequate measurements were obtained in each tibia. In patients without Paget's disease (7 men and 4 women; mean age, 61.9 years; range, 51 to 72 years), there was no difference in mean bone material strength index (BMSi) between the dominant and nondominant leg (82.1 ± 1.3 and 81.4 ± 1.3, respectively; p = 0.606). In each individual subject studied, sequential indentations in both legs showed no trends for higher or lower values with time. The standard deviation of unnormalized bone material strength (BMSu) was also comparable between the dominant and nondominant tibia (5.3 and 4.5, respectively; p = 0.657). In patients with Paget's disease (4 men and 5 women; mean age, 69.5 years; range, 55 to 87 years), mean BMSi of the Pagetic tibia was lower, albeit nonsignificantly, than that of the contralateral nonaffected tibia (74.7 ± 1.7 and 78.7 ± 1.3, respectively; p = 0.120). In contrast to subjects without Paget's disease, the SD of adequate BMSu values was significantly larger in the Pagetic tibia compared to that of the non‐Pagetic tibia (7.6 versus 5.0, respectively, p = 0.008). These results highlight the consistency of serial IMI measurements as performed by a single operator in the presence as well as absence of tibia pathology and illustrate that the method is able to capture alterations of tissue‐level cortical bone properties in patients with Paget's disease of the tibia. © 2017 The Authors.Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

True Gold or Pyrite: A Review of Reference Point Indentation for Assessing Bone Mechanical Properties In Vivo

Although the gold standard for determining bones' mechanical integrity is the direct measure of mechanical properties, clinical evaluation has long relied on surrogates of mechanical properties for assessment of fracture risk. Nearly a decade ago, reference point indentation (RPI) emerged as an innovative way to potentially assess mechanical properties of bone in vivo. Beginning with the BioDent device, and then followed by the newer generation OsteoProbe, this RPI technology has been utilized in several publications. In this review we present an overview of the technology and some important details about the two devices. We also highlight select key studies, focused specifically on the in vivo application of these devices, as a way of synthesizing where the technology stands in 2015. The BioDent machine has been shown, in two clinical reports, to be able to differentiate fracture versus nonfracture patient populations and in preclinical studies to detect treatment effects that are consistent with those quantified using traditional mechanical tests. The OsteoProbe appears able to separate clinical cohorts yet there exists a lack of clarity regarding details of testing, which suggests more rigorous work needs to be undertaken with this machine. Taken together, RPI technology has shown promising results, yet much more work is needed to determine if its theoretical potential to assess mechanical properties in vivo can be realized. © 2015 American Society for Bone and Mineral Research.     

Microindentation for in vivo measurement of bone tissue material properties in atypical femoral fracture patients and controls

Atypical femoral fractures (AFF) associated with long‐term bisphosphonates (LTB) are a growing concern. Their etiology is unknown, but bone material properties might be deteriorated. In an AFF series, we analyzed the bone material properties by microindentation. Four groups of patients were included: 6 AFF, 38 typical osteoporotic fractures, 6 LTB, and 20 controls without fracture. Neither typical osteoporotic fractures nor controls have received any antiosteoporotic medication. A general laboratory workup, bone densitometry by dual‐energy X‐ray absorptiometry (DXA), and microindentation testing at the tibia were done in all patients. Total indentation distance (Total ID), indentation distance increase (IDI), and creep indentation distance (Creep ID) were measured (microns). Age‐adjusted analysis of covariance (ANCOVA) was used for comparisons. Controls were significantly younger than fracture groups. Bisphosphonate exposure was on average 5.5 years (range 5 to 12 years) for the AFF and 5.4 years (range 5 to 8 years) for the LTB groups. Total ID (microns) showed better material properties (lower Total ID) for controls 36 (± 6; mean ± SD) than for AFF 46 (± 4) and for typical femoral fractures 47 (± 13), respectively. Patients on LTB showed values between controls and fractures, 38 (± 4), although not significantly different from any of the other three groups. IDI values showed a similar pattern 13 (± 2), 16 (± 6), 19 (± 3), and 18 (± 5). After adjusting by age, significant differences were seen between controls and typical (p < 0.001) and atypical fractures (p = 0.03) for Total ID and for IDI (p < 0.001 and p < 0.05, respectively). There were no differences in Creep ID between groups. Our data suggest that patients with AFF have a deep deterioration in bone material properties at a tissue level similar to that for the osteoporotic fracture group. The LTB group shows levels that are in between controls and both type of fractures, although not statistically different. These results suggest that bisphosphonate therapy probably does not put the majority of patients at risk for AFF. © 2013 American Society for Bone and Mineral Research     

Duration-Dependent Increase of Human Bone Matrix Mineralization in Long-Term Bisphosphonate Users with Atypical Femur Fracture

Bisphosphonates (BPs) are the most widely used drugs for the treatment of osteoporosis but prolonged use of BPs might increase the risk of atypical femur fracture (AFF). There are only a few studies that address the bone material quality in patients on long-term BP treatment with or without AFFs. We analyzed 52 trans-iliac bone biopsies from patients on long-term BP therapy with (n = 26) and without (n = 26) AFF. At the microscopic level, the degree of mineralization of bone (DMB) was assessed on whole bone by X-ray digitized microradiography while microhardness by Vickers microindentation, and bone matrix characteristics by Fourier transform infrared microspectroscopy (FTIRM) (mineral/organic ratio, mineral maturity and crystallinity, and collagen maturity) were measured at random focal areas. The AFF patients were treated longer than non-AFF patients (9.7 ± 3.3 years versus 7.9 ± 2.7 years). As expected, bone remodeling was low in both groups, without difference between them. The AFF group had significantly higher DMB in cortical bone (+2.9%, p = .001), which remained so after adjusting for treatment duration (p = .007), and showed a trend in cancellous bone (+1.6%, p = .05). Consistent with higher DMB, heterogeneity index (HI) was lower in the AFF than in the non-AFF group, illustrating lower heterogeneity of mineralization in the AFF group. A significant positive correlation between the duration of treatment and DMB in cortical bone was found in AFF, and not in the non-AFF group. Microhardness and bone matrix characteristics were similar between groups. We conclude that the AFF group had a duration-dependent increase in DMB leading to a significantly higher DMB than the non-AFF. Because BPs have high affinity to bone mineral and lining the walls of the osteocyte lacunae, the accumulation of matrix-bound BPs in AFF could lead to inhibition of the osteocyte cytoskeleton blunting their response to mechanical strains, a hypothesis to be further investigated. © 2021 American Society for Bone and Mineral Research (ASBMR).     

In Vivo Assessment of Bone Quality in Postmenopausal Women With Type 2 Diabetes

Although patients with type 2 diabetes (T2D) are at significant risk for well‐recognized diabetic complications, including macrovascular disease, retinopathy, nephropathy, and neuropathy, it is also clear that T2D patients are at increased risk for fragility fractures. Furthermore, fragility fractures in patients with T2D occur at higher bone mineral density (BMD) values compared to nondiabetic controls, suggesting abnormalities in bone material strength (BMS) and/or bone microarchitecture (bone “quality”). Thus, we performed in vivo microindentation testing of the tibia to directly measure BMS in 60 postmenopausal women (age range, 50–80 years) including 30 patients diagnosed with T2D for >10 years and 30 age‐matched, nondiabetic controls. Regional BMD was measured by dual‐energy X‐ray absorptiometry (DXA); cortical and trabecular bone microarchitecture was assessed from high‐resolution peripheral quantitative computed tomography (HRpQCT) images of the distal radius and tibia. Compared to controls, T2D patients had significantly lower BMS: unadjusted (?11.7%; p < 0.001); following adjustment for body mass index (BMI) (?10.5%; p < 0.001); and following additional adjustment for age, hypertension, nephropathy, neuropathy, retinopathy, and vascular disease (?9.2%; p = 0.022). By contrast, after adjustment for confounding by BMI, T2D patients had bone microarchitecture and BMD that were not significantly different than controls; however, radial cortical porosity tended to be higher in the T2D patients. In addition, patients with T2D had significantly reduced serum markers of bone turnover (all p < 0.001) compared to controls. Of note, in patients with T2D, the average glycated hemoglobin level over the previous 10 years was negatively correlated with BMS (r = ?0.41; p = 0.026). In conclusion, these findings represent the first demonstration of compromised BMS in patients with T2D. Furthermore, our results confirm previous studies demonstrating low bone turnover in patients with T2D and highlight the potential detrimental effects of prolonged hyperglycemia on bone quality. Thus, the skeleton needs to be recognized as another important target tissue subject to diabetic complications. © 2014 American Society for Bone and Mineral Research.     

Assessment of Bone Health in Patients With Type 1 Gaucher Disease Using Impact Microindentation

Gaucher disease (GD), one of the most common lysosomal disorders (a global population incidence of 1:50,000), is characterized by beta‐glucocerebrosidase deficiency. Some studies have demonstrated bone infiltration in up to 80% of patients, even if asymptomatic. Bone disorder remains the main cause of morbidity in these patients, along with osteoporosis, avascular necrosis, and bone infarcts. Enzyme replacement therapy (ERT) has been shown to improve these symptoms. This cross‐sectional study included patients with type 1 Gaucher disease (GD1) selected from the Catalan Study Group on GD. Clinical data were collected and a general laboratory workup was performed. Bone mineral density (BMD) was measured at the lumbar spine and hip using dual‐energy X‐ray absorptiometry (DXA). Patients with bone infarcts or any other focal lesion in the area of indentation visible on imaging were excluded. Bone Material Strength index (BMSi) was measured by bone impact microindentation using an Osteoprobe instrument. Analysis of covariance (ANCOVA) models were fitted to adjust for age, sex, weight, and height. Sixteen patients with GD1 and 29 age‐ and sex‐matched controls were included. GD1 was associated with significantly lower BMSi (adjusted beta –9.30; 95% CI, –15.18 to –3.42; p = 0.004) and reduced lumbar BMD (adjusted beta –0.14; 95% CI, –0.22 to –0.06; p = 0.002) and total hip BMD (adjusted beta –0.09; 95% CI, –0.15 to –0.03; p = 0.006), compared to GD1‐free controls. Chitotriosidase levels were negatively correlated with BMSi (linear R² = 51.6%, p = 0.004). Bone tissue mechanical characteristics were deteriorated in patients with GD1. BMSi was correlated with chitotriosidase, the marker of GD activity. Bone disorder requires special consideration in this group of patients, and microindentation could be an appropriate tool for assessing and managing their bone health. © 2017 American Society for Bone and Mineral Research.     

High‐Impact Mechanical Loading Increases Bone Material Strength in Postmenopausal Women—A 3‐Month Intervention Study

Bone adapts to loading in several ways, including redistributing bone mass and altered geometry and microarchitecture. Because of previous methodological limitations, it is not known how the bone material strength is affected by mechanical loading in humans. The aim of this study was to investigate the effect of a 3‐month unilateral high‐impact exercise program on bone material properties and microarchitecture in healthy postmenopausal women. A total of 20 healthy and inactive postmenopausal women (aged 55.6 ± 2.3 years [mean ± SD]) were included and asked to perform an exercise program of daily one‐legged jumps (with incremental number, from 3×10 to 4×20 jumps/d) during 3 months. All participants were asked to register their performed jumps in a structured daily diary. The participants chose one leg as the intervention leg and the other leg was used as control. The operators were blinded to the participant's choice of leg for intervention. The predefined primary outcome was change in bone material strength index (BMSi), measured at the mid tibia with a handheld reference probe indentation instrument (OsteoProbe). Bone microstructure, geometry, and density were measured with high‐resolution peripheral quantitative computed tomography (XtremeCT) at the ultradistal and at 14% of the tibia bone length (distal). Differences were analyzed by related samples Wilcoxon signed rank test. The overall compliance to the jumping program was 93.6%. Relative to the control leg, BMSi of the intervention leg increased 7% or 0.89 SD (p = 0.046), but no differences were found for any of the XtremeCT‐derived bone parameters. In conclusion, a unilateral high‐impact loading program increased BMSi in postmenopausal women rapidly without affecting bone microstructure, geometry, or density, indicating that intense mechanical loading has the ability to rapidly improve bone material properties before changes in bone mass or structure. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

Bone Mineral and Organic Properties in Postmenopausal Women Treated With Denosumab for Up to 10 years

In postmenopausal women with osteoporosis, denosumab (DMAb) therapy through 10 years resulted in significantly higher degree of mineralization of bone, with a subsequent increase from years 2–3 to year 5 and no further difference between years 5 and 10. Our aim was to assess the variables reflecting the quality of bone mineral and organic matrix (Fourier transform infrared microspectroscopy), and the microhardness of bone (Vickers microindentation). Cross-sectional assessments were performed in blinded fashion on iliac bone biopsies from osteoporotic women (72 from FREEDOM trial, 49 from FREEDOM Extension trial), separately in cortical and cancellous compartments. After 2–3 years of DMAb, mineral/matrix ratio and microhardness of cortical bone were significantly higher compared with placebo, whereas mineral maturity, mineral crystallinity, mineral carbonation, and collagen maturity were not different in both bone compartments. Through 5 years of DMAb, mineral carbonation was significantly lower and mineral/matrix ratio, mineral maturity, and crystallinity were significantly higher versus 2–3 years and were not different between 5 and 10 years, with the exception of mineral maturity in cancellous bone. These data support a transition of mineral to more mature crystals (within physiological range) and the completeness of secondary mineralization within 5 years of DMAb treatment. Microhardness in cortical and cancellous compartments was significantly lower at 5 years of DMAb versus 2–3 years and was not different from years 5 to 10. The lower microhardness at years 5 and 10 is likely the result of maturation of the organic matrix in a persistently low state of bone remodeling over 5 and 10 years. © 2022 American Society for Bone and Mineral Research (ASBMR).