Usefulness of Trabecular Bone Score (TBS) to Identify Bone Fragility in Patients with Primary Hyperparathyroidism

Background: Patients with primary hyperparathyroidism usually show decreased bone strength that are often not well diagnosed by conventional Dual-energy X-ray absorptiometry (DXA). Trabecular Bone Score (TBS) is a new technique for assessing bone microarchitecture indirectly. This cross-sectional study evaluates the usefulness of TBS in patients with primary hyperparathyroidism in clinical practice. Methodology: Bone mineral density (BMD) by DXA and TBS values by TBS InSight® software were determined in 72 patients with primary hyperparathyroidism to analyze its relationship with fragility fractures. A receiver operating curve was performed to evaluate the usefulness of TBS as predictor of fragility fractures. FRAX index with and without adjustment by TBS was calculated. Additionally, longitudinal data of a subgroup of patients according to the therapeutic management were also evaluated. Results: A total of 51.4% of the patients showed degraded microarchitecture while only 37.5% of them were diagnosed of osteoporosis by DXA. No significant correlation was found between TBS values and BMD parameters. However, TBS values were lower in osteoporotic patients compared to those classified as normal by BMD (1.16 ± 0.12vs 1.26 ± 0.17; p?=?0.043) and in patients with fragility fractures compared to nonfractured patients (1.19 ± 0.03vs 1.24 ± 0.02, p < 0.001). The area under the curve for TBS performed better than the combination of femoral, hip and spine-BMD for prevalent fractures (0.714vs 0.679). TBS-adjusted FRAX was higher than nonadjusted model for both major osteoporotic and hip fracture (4.5% vs 3%; 0.9% vs 0.7%; p < 0.001). At follow-up, an improvement in TBS values was observed in treated patients (medical or surgical) vs nontreated close to significance (1.27 ± 0.10vs 1.24 ± 0.11, p?=?0.074). Conclusions: TBS could be a useful tool to identify increased fracture risk in patients with primary hyperparathyroidism underdiagnosed by BMD. Moreover, FRAX adjusted by TBS could be a more robust tool for predicting the risk of osteoporotic fracture to help in therapeutic decisions in this population.     

Type 1 Diabetes in Young Rats Leads to Progressive Trabecular Bone Loss,Cessation of Cortical Bone Growth,and Diminished Whole Bone Strength and Fatigue Life

People with diabetes have increased risk of fracture disproportionate to BMD, suggesting reduced material strength (quality). We quantified the skeletal effects of type 1 diabetes in the rat. Fischer 344 and Sprague‐Dawley rats (12 wk of age) were injected with either vehicle (Control) or streptozotocin (Diabetic). Forelimbs were scanned at 0, 4, 8, and 12 wk using pQCT. Rats were killed after 12 wk. We observed progressive osteopenia in diabetic rats. Trabecular osteopenia was caused by bone loss: volumetric BMD decreased progressively with time in diabetic rats but was constant in controls. Cortical osteopenia was caused by premature arrest of cortical expansion: cortical area did not increase after 4–8 wk in diabetic rats but continued to increase in controls. Postmortem μCT showed a 60% reduction in proximal tibial trabecular BV/TV in diabetic versus control rats, whereas moments of inertia of the ulnar and femoral diaphysis were reduced ～30%. Monotonic bending tests indicated that ulna and femora from diabetic animals were ～25% less stiff and strong versus controls. Estimates of material properties indicated no changes in elastic modulus or ultimate stress but modest (～10%) declines in yield stress for diabetic bone. These changes were associated with a ～50% increase in the nonenzymatic collagen cross‐link pentosidine. Last, cyclic testing showed diminished fatigue life in diabetic bones at the structural (force) level but not at the material (stress) level. In summary, type 1 diabetes, left untreated, causes trabecular bone loss and a reduction in diaphyseal growth. Diabetic bone has greatly increased nonenzymatic collagen cross‐links but only modestly reduced material properties. The loss of whole bone strength under both monotonic and fatigue loading is attributed mainly to reduced bone size.     

Birth Weight Is Not Associated With Risk of Fracture: Results From Two Swedish Cohort Studies

Development and growth in utero has been suggested to influence bone health. However, the relationship with risk of fracture in old age is largely unknown. Using Cox proportional hazards regression, we studied the association between birth weight and fractures at ages 50–94 among 10,893 men and women (48% women) from the Uppsala Birth Cohort Study (UBCoS, born 1915–29) and 1334 men from the Uppsala Longitudinal Study of Adult Men (ULSAM, born 1920–24). Measured birth weight was collected from hospital or midwives' records and fractures from the Swedish National Patient Register. We observed 2796 fractures (717 of these were hip fractures) in UBCoS and 335 fractures (102 hip fractures) in ULSAM. In UBCoS, the hazard ratio (HR) per 1 kg increase in birth weight, adjusted for sex and socioeconomic status at birth, was 1.01 [95% confidence interval (CI), 0.94–1.09] for any fracture and 1.06 (95% CI, 0.91–1.23) for hip fracture. Estimates in ULSAM were similar. We did not observe a differential association of birth weight with fractures occurring before age 70 or after age 70 years. Neither birth weight standardized for gestational age nor gestational duration was associated with fracture rate. In linear regression, birth weight was not associated with bone mineral density among 303 men who were 82‐years‐old in ULSAM but showed positive associations with total body bone mineral content (β per kg increase in birth weight, adjusted for social class and age, 133; 95% CI, 30–227). This association was attenuated after further adjustment for body mass index and height (β, 41; 95% CI, ‐43–126). We conclude that birth weight is associated with bone mineral content but this association does not translate into an association with risk of fracture in men and women aged 50–94 years. © 2014 American Society for Bone and Mineral Research.     

Effects of preexisting microdamage,collagen cross‐links,degree of mineralization,age, and architecture on compressive mechanical properties of elderly human vertebral trabecular bone

Previous studies have shown that the mechanical properties of trabecular bone are determined by bone volume fraction (BV/TV) and microarchitecture. The purpose of this study was to explore other possible determinants of the mechanical properties of vertebral trabecular bone, namely collagen cross‐link content, microdamage, and mineralization. Trabecular bone cores were collected from human L2 vertebrae (n = 49) from recently deceased donors 54–95 years of age (21 men and 27 women). Two trabecular cores were obtained from each vertebra, one for preexisting microdamage and mineralization measurements, and one for BV/TV and quasi‐static compression tests. Collagen cross‐link content (PYD, DPD, and PEN) was measured on surrounding trabecular bone. Advancing age was associated with impaired mechanical properties, and with increased microdamage, even after adjustment by BV/TV. BV/TV was the strongest determinant of elastic modulus and ultimate strength (r² = 0.44 and 0.55, respectively). Microdamage, mineralization parameters, and collagen cross‐link content were not associated with mechanical properties. These data indicate that the compressive strength of human vertebral trabecular bone is primarily determined by the amount of trabecular bone, and notably unaffected by normal variation in other factors, such as cross‐link profile, microdamage and mineralization. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:481–488, 2011     

Cross‐link stabilization does not affect the response of collagen molecules,fibrils, or tendons to tensile overload

We investigated whether immature allysine‐derived cross‐links provide mechanically labile linkages by exploring the effects of immature cross‐link stabilization at three levels of collagen hierarchy: damaged fibril morphology, whole tendon mechanics, and molecular stability. Tendons from the tails of young adult steers were either treated with sodium borohydride (NaBH₄) to stabilize labile cross‐links, exposed only to the buffer used during stabilization treatment, or maintained as untreated controls. One‐half of each tendon was then subjected to five cycles of subrupture overload. Morphologic changes to collagen fibrils resulting from overload were investigated using scanning electron microscopy, and changes in the hydrothermal stability of collagen molecules were assessed using hydrothermal isometric tension testing. NaBH₄ cross‐link stabilization did not affect the response of tendon collagen to tensile overload at any of the three levels of hierarchy studied. Cross‐link stabilization did not prevent the characteristic overload‐induced mode of fibril damage that we term discrete plasticity. Similarly, stabilization did not alter the mechanical response of whole tendons to overload, and did not prevent an overload‐induced thermal destabilization of collagen molecules. Our results indicate that hydrothermally labile cross‐links may not be as mechanically labile as was previously thought. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1907–1913, 2013     

Peripheral Quantitative Computed Tomography (pQCT) Measures Contribute to the Understanding of Bone Fragility in Older Patients With Low-trauma Fracture

Dual-energy X-ray absorptiometry (DXA) as currently used has limitations in identifying patients with osteoporosis and predicting occurrence of fracture. We aimed to express peripheral quantitative computed tomography (pQCT) variables of patients with low-trauma fracture as T-scores by using T-score scales obtained from healthy young women, and to evaluate the potential clinical utility of pQCT for the assessment of bone fragility. Fracture patients were recruited from a fracture liaison service at the Royal Melbourne Hospital. Reference pQCT data were obtained from studies on women's health conducted by our group. A study visit was arranged with fracture patients, during which DXA and pQCT were applied to measure their bone strength. A total of 59 fracture patients were recruited, and reference data were obtained from 78 healthy young females. All DXA variables and most pQCT variables were significantly different between healthy young females and fracture patients (p?<?0.05), except polar stress-strain index (p?=?0.34) and cortical bone density (p?=?0.19). Fracture patients were divided into osteoporosis and non-osteoporosis groups according to their DXA T-scores. Significant differences were observed in most pQCT variables (p?<?0.05), except trabecular area and cortical density (p?>?0.9 and p?=?0.5, respectively). By applying pQCT T-scores, 11 (27%) of patients who were classified as having low or medium risk of osteoporosis on DXA T-scores alone were reclassified as high risk. Results of logistic regression suggested trabecular bone density as an independent predictor of osteoporosis status. More patients can be identified with osteoporosis by applying pQCT T-score variables in older people with low-trauma fracture. Peripheral QCT T-scores contribute to the understanding of bone fragility in this population.     

Postmenopausal Women With Colles'' Fracture Have Lower Values of Bone Mineral Density Than Controls as Measured by Quantitative Ultrasound and Densitometry

Measurement of ultrasonographic parameters provides information concerning not only bone density but also bone architecture. We investigated the usefulness of ultrasonographic parameters and bone mineral density (BMD) to evaluate the probability of Colles' fracture. Two-hundred eighty-nine postmenopausal women (62.3 +/- 8.7 yr) with (n = 76) and without (n = 213) Colles' fracture were studied. BMD of lumbar spine and proximal femur was evaluated in all women by dual-energy X-ray absorptiometry (DXA) and speed of sound (SOS), broadband ultrasound attenuation (BUA), and stiffness in the calcaneus were measured by a Sahara ultrasonometer (Hologic). Patients suffering from Colles' fracture had lower values of BMD adjusted by height at the lumbar spine, L2-L4 (0.797 g/cm2 vs 0.860 g/cm2), femoral neck (0.685 g/cm2 vs 0.712 g/cm2 ), SOS (1518 m/sg vs 1525 m/sg), and stiffness (74.6 vs 77.7) (p < 0.05). Nevertheless, BUA values were similar in both groups. After stepwise logistic regression analysis, the area found under receiver operating characteristic (ROC) curves was 0.60 for L2L4 and 0.63 for a formula combining L2L4 and height. Our data suggest that patients suffering from Colles' fracture have lower values of BMD by DXA, SOS, and stiffness. However, the ability of these techniques to discriminate is low because the values for the area under ROC curve are 0.60 for L2-L4 and 0.63 for a formula derived of the combination of L2-L4 and height.     

Effects of Yearly Zoledronic Acid 5 mg on Bone Turnover Markers and Relation of PINP With Fracture Reduction in Postmenopausal Women With Osteoporosis

In patients with osteoporosis treated with antiresorptive agents, reduction in bone turnover explains much of the observed fracture risk reduction. Lower levels of bone turnover markers (BTMs) appear to be associated with a lower risk of fracture in bisphosphonate‐treated patients. BTMs were measured in a subset of subjects in the HORIZON Pivotal Fracture Trial. Annual infusions of zoledronic acid 5 mg significantly reduced BTMs: median decrease of 50% for β‐C‐terminal telopeptides of type 1 collagen (β‐CTX), 30% for bone alkaline phosphatase (ALP), and 56% for procollagen type 1 amino‐terminal propeptide (PINP). The mean level of BTMs decreased in treated patients but remained within the premenopausal range before the next injection. The percentage of zoledronic acid–treated patients with values below the premenopausal reference range at all time points was 1.7%, 17.8%, and 19% for bone ALP, CTX, and PINP, respectively. The third injection of zoledronic acid resulted in 60% reduction of β‐CTX within 9–11 days, followed by a gradual increase, indicating the persistence of osteoclastic bone resorption. The association between changes in BTMs and fracture incidence was assessed in 1132 patients who had PINP measurements at baseline and 1 yr. There was no association between low PINP levels at 1 yr and increased fracture incidence. In summary, (1) annual injections of zoledronic acid reduced BTMs in the premenopausal range, with a significant response persisting after the third infusion; and (2) low levels of PINP were not associated with increased fracture risk.     

Relationship of Spinal Fracture to Bone Density,Textural, and Anthropometric Parameters

To investigate risk factors for spinal fracture, we studied the relationship between the prevalence of asymptomatic spinal fracture and various morphological measures including spinal bone mineral density (BMD) in women. A total of 122 women ranging in age from 55 to 79 years were studied. The group consisted of 46 women aged 55–59 years (18 with fracture), 51 women aged 60–69 years (26 with fracture), and 26 women aged 70–79 years (14 with fracture). BMD of cortical and trabecular bone from L1 to L3 was measured using quantitative computed tomography (QCT). Run-length analysis was applied to evaluate the spinal trabecular textural features using CT images; the texture indices which represent the mean width of trabeculae (the T-texture) and that of intertrabecular spaces (the I-texture) were obtained. Anthropometric factors including body weight and height, psoas muscle area, and vertebral bone volume were measured using CT images. Among the various factors, trabecular BMD in women aged 55–69 years showed the highest odds ratio for the presence of fracture per standard deviation (SD) decrease in bone density. However, in women aged 70–79 years, the highest odds ratio was observed for trabecular texture index but not for trabecular BMD. The I-texture in women aged 55–59 years, the muscle area in women aged 60–69 years, and cortical BMD and muscle area in women aged 70–79 years were also considered significantly related to the risk of fracture. Received: 31 December 1995 / Accepted: 24 July 1996     

Use of Clinical Risk Factors in Elderly Women with Low Bone Mineral Density to Identify Women at Higher Risk of Hip Fracture: The EPIDOS Prospective Study

Elderly women with very low bone mineral density (BMD) (T-score ≤−3.5) have a risk of hip fracture more than two times higher than the average risk of women of the same age. Using data from the EPIDOS prospective study, we have shown that by measuring BMD on the 50% of women who have the lowest weight, it is possible to identify the majority of these women at higher risk. In the present analysis, we assessed whether the use of clinical risk factors, in the subset of women selected for osteodensitometry and with moderately low BMD (T-score between −3.5 and −2.5), allows the identification of another subgroup of women with a risk 2 times higher than average and, thereby, increases the efficiency of selective BMD screening. We then assessed the discriminant value for hip fracture of the overall screening strategy (i.e., use of weight to select women for osteodensitometry, then use of clinical risk factors to enhance the predictive value of BMD), and compared it with the value of BMD used as a population screening tool. In total, 6933 EPIDOS participants, aged 75 years or above, were included in this analysis. Using Cox regression models, we first determined which baseline factors were most predictive of hip fracture among the 1588 women with weight below median (selection criteria for osteodensitometry in the proposed strategy) and T-score between −3.5 and −2.5. Based on the relative risk (RR) estimates from the final risk function, we calculated an individual risk score for hip fracture. We assessed the incidence of hip fracture for each value of the score, and determined the cutoff to identify women with a risk about 2 times higher than the average risk in this elderly cohort. The overall screening strategy (i.e., selective BMD measurement based on weight, followed by clinical fracture risk assessment) identifies two subgroups of higher risk women: a group with very low BMD (T-score ≤–3.5), and another group with moderately low BMD (T-score between –3.5 and –2.5) but a high fracture risk score. We calculated the total number of women classified as being at high risk, and assessed the overall sensitivity and specificity of this strategy to identify elderly women who will suffer a hip fracture. Among women with weight below median and T-score between −3.5 and −2.5, the factors most predictive of the risk of hip fracture were age, history of fall, ability to do the tandem walk (test of dynamic balance), gait speed and visual acuity. A simple additive score based on these factors (except visual acuity) allows a high-risk group (risk about 2 times higher than average) to be clearly distinguished from a low-risk group (risk below average). Overall, the proposed strategy identifies approximately 15% of the women in the cohort as being at high risk, i.e., 543 women with T-score ≤−3.5 and 503 women with −3.5 <T-score ≤−2.5 and a high fracture risk score. The sensitivity for hip fracture is equal to 37% and the specificity to 85%, which is equivalent to the discriminant value of BMD as a population screening tool. In elderly women, the use of a simple clinical risk score, in women with previous BMD values, allows the number of high-risk women identified to be increased. Overall, the proposed screening strategy (use of weight to select women for osteodensitometry, and then use of clinical risk factors to enhance the predictive value of BMD) has the same discriminant value for hip fracture as BMD used as a population screening tool. Received: 20 November 2001 / Accepted: 11 February 2002     

Use of high resolution dual‐energy x‐ray absorptiometry‐region free analysis (DXA‐RFA) to detect local periprosthetic bone remodeling events

Dual‐energy x‐ray absorptiometry (DXA) is the gold standard method for measuring periprosthetic bone remodeling, but relies on a region of interest (ROI) analysis approach. While this addresses issues of anatomic variability, it is insensitive to bone remodeling events at the sub‐ROI level. We have validated a high‐spatial resolution tool, termed DXA‐region free analysis (DXA‐RFA) that uses advanced image processing approaches to allow quantitation of bone mineral density (BMD) at the individual pixel (data‐point) level. Here we compared the resolution of bone remodeling measurements made around a stemless femoral prosthesis in 18 subjects over 24 months using ROI‐based analysis versus that made using DXA‐RFA. Using the ROI approach the regional pattern of BMD change varied by region, with greatest loss in ROI5 (20%, p < 0.001), and largest gain in ROI4 (6%, p < 0.05). Analysis using DXA‐RFA showed a focal zone of increased BMD localized to the prosthesis–bone interface (30–40%, p < 0.001) that was not resolved using conventional DXA analysis. The 20% bone loss observed in ROI5 with conventional DXA was resolved to a focal area adjacent to the cut surface of the infero‐medial femoral neck (up to 40%, p < 0.0001). DXA‐RFA enables high resolution analysis of DXA datasets without the limitations incurred using ROI‐based approaches. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:712–716, 2015.     

The Correction of Systematic Error due to Plaster and Fiberglass Casts on HR-pQCT Bone Parameters Measured In Vivo at the Distal Radius

Due to difficulty assessing healing of distal radius fractures using conventional radiography, there is interest in using high resolution peripheral quantitative computed tomography (HR-pQCT) to track healing at the microarchitectural level. Unfortunately, the plaster-of-Paris and fiberglass casts used to immobilize fractures affect HR-pQCT measurements due to beam hardening, and increased noise. The challenge is compounded because casts have variable thickness, and an individual patient will often have their cast changed 2–3 times during the course of treatment. This study quantifies the effect of casts within a clinically relevant range of thicknesses on measured bone parameters at the distal radius, and establishes conversion equations to correct for systematic error in due to cast presence. Eighteen nonfractured participants were scanned by HR-pQCT in three conditions: no cast, plaster-of-Paris cast, and fiberglass cast. Measured parameters were compared between the baseline scan (no cast) and each cast scan to evaluate if systematic error exists due to cast presence. A linear regression model was used to determine an appropriate conversion for parameters that were found to have systematic error. Plaster-of-Paris casts had a greater range of thicknesses (3.2–9.5 mm) than the fiberglass casts (3.0–5.4 mm), and induced a greater magnitude of systematic error overall. Key parameters of interest were bone mineral density (total, cortical, and trabecular) and trabecular bone volume fraction, all of which were found to have systematic error due to presence of either cast type. Linear correlations between baseline and cast scans for these parameters were excellent (R² > 0.98), and appropriate conversions could be determined within a margin of error less than a ±6% for the plaster-of-Paris cast, and ±4% for the fiberglass cast. We have demonstrated the effects of cast presence on bone microarchitecture measurements, and presented a method to correct for systematic error, in support of future use of HR-pQCT to study fracture healing.