J. Haschka

TBS reflects trabecular microarchitecture in premenopausal women and men with idiopathic osteoporosis and low-traumatic fractures

Transiliac bone biopsies, while widely considered to be the standard for the analysis of bone microstructure, are typically restricted to specialized centers. The benefit of Trabecular Bone Score (TBS) in addition to areal bone mineral density (aBMD) for fracture risk assessment has been documented in cross-sectional and prospective studies. The aim of this study was to test if TBS may be useful as a surrogate to histomorphometric trabecular parameters of transiliac bone biopsies. Transiliac bone biopsies from 80 female patients (median age 39.9 years-interquartile range, IQR 34.7; 44.3) and 43 male patients (median age 42.7 years-IQR 38.9; 49.0) with idiopathic osteoporosis and low traumatic fractures were included. Micro-computed tomography values of bone volume fraction (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp), structural model index (SMI) as well as serum bone turnover markers (BTMs) sclerostin, intact N-terminal type 1 procollagen propeptide (P1NP) and cross-linked C-telopeptide (CTX) were investigated. TBS values were higher in females (1.282 vs 1.169, p< 0.0001) with no differences in spine aBMD, whereas sclerostin levels (45.5 vs 33.4 pmol/L) and aBMD values at the total hip (0.989 vs 0.971 g/cm(2), p<0.001 for all) were higher in males. Multiple regression models including: gender, aBMD and BTMs revealed TBS as an independent, discriminative variable with adjusted multiple R(2) values of 69.1% for SMI, 79.5% for Tb.N, 68.4% for Tb.Sp, and 83.3% for BV/TV. In univariate regression models, BTMs showed statistically significant results, whereas in the multiple models only P1NP and CTX were significant for Tb.N. TBS is a practical, non-invasive, surrogate technique for the assessment of cancellous bone microarchitecture and should be implemented as an additional tool for the determination of trabecular bone properties.

The Impact of Vitamin D, Calcium, Protein Supplementation, and Physical Exercise on Bone Metabolism After Bariatric Surgery: The BABS Study

Laparoscopic Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are common and effective methods to treat severe obesity, but these procedures can adversely influence bone metabolism and areal bone mineral density (aBMD). This was a prospective 24-month single-center interventional two-arm study in 220 women and similarly aged men (median age 40.7 years) with a body mass index (BMI) >38 kg/m(2) after RYGB and SG procedures. Patients were randomized into: 1) an intervention group receiving: 28,000 IU cholecalciferol/wk for 8 weeks before bariatric surgery, 16,000 IU/wk and 1000 mg calciummonocitrate/d after surgery, daily BMI-adjusted protein supplementation and physical exercise (Nordic walking, strength perseverance, and equipment training); 2) a non-intervention group: no preoperative loading, nutritional supplementation, or obligatory physical exercise. At study endpoint, when comparing the intervention group to the non-intervention group, the relative percentage changes of serum levels of sclerostin (12.1% versus 63.8%), cross-linked C-telopeptide (CTX, 82.6% versus 158.3%), 25-OH vitamin D (13.4% versus 18.2%), phosphate (23.7% versus 32%, p < 0.001 for all), procollagen type 1 amino-terminal propeptide (P1NP, 12% versus 41.2%), intact parathyroid hormone (iPTH, -17.3% versus -7.6%), and Dickkopf-1 (-3.9% versus -8.9%, p < 0.05 for all) differed. The decline in lumbar spine, total hip and total body aBMD, changes in BMI, lean body mass (LBM), as well as changes in trabecular bone score (TBS) values (p < 0.005 for all) were less, but significantly, pronounced in the intervention group. We conclude that vitamin D loading and ongoing vitamin D, calcium, and BMI-adjusted protein supplementation in combination with physical exercise decelerates the loss of aBMD and LBM after bariatric surgery. Moreover, the well-known increases of bone turnover markers are less pronounced.

Overlapping and continued alendronate or raloxifene administration in patients on teriparatide: effects on areal and volumetric bone mineral density--the CONFORS Study.

Nine month teriparatide (TPTD) monotherapy followed by co‐administration of raloxifene (RAL) or alendronate (ALN) for another nine 9 months resulted in incremental bone mineral density (BMD) increase. The aim of this study was to investigate the effects of continued antiresorptive treatments for 12 months in the extension phase. Postmenopausal women (n = 125) with severe osteoporosis on ongoing TPTD treatment for 9 months were randomized into three open‐label groups for another 9 months: ALN (70 mg/week, n = 41), RAL (60 mg/d, n = 37) in addition to TPTD or no additional medication (n = 47) except Ca and vitamin D. After discontinuation of TPTD the respective antiresorptives were continued for a further 12 months, while patients in the TPTD monotherapy group received Ca and vitamin D. Amino‐terminal propeptide of type I procollagen (P1NP) and cross‐linked C‐telopeptide (CTX), areal and volumetric BMD at the lumbar spine (LS) and hip were assessed. ALN resulted in continued BMD increase in LS (4.3 ± 1.5%; mean ± SD), femoral neck (4.2 ± 1.6%) and total hip (4 ± 1.6%; p < 0.001 for all), while RAL was only effective at the LS (2.4 ± 1.7%, p < 0.001) but no changes at the femoral neck (0.4 ± 1.4%) or total hip (−0.8 ± 1.5%) were observed. Cortical bone only increased in the ALN group (femoral neck 6.7 ± 2.7% and −1.3 ± 2.5%; total hip 13.8 ± 2.9% and −2.3 ± 2.5% for ALN and RAL, p < 0.001 for all; respectively). Analyzing the entire 30 months of therapy, the ALN group revealed the largest BMD increase in all regions. Our results suggest that the addition of ALN to ongoing TPTD and continuing ALN after TPTD was stopped may be beneficial for patients in terms of areal and volumetric BMD increase. Further research is warranted to determine the optimal timing of the initiation of the combination treatment, the respective antiresorptive medication and the potential benefit of this BMD increase regarding fracture prevention.

Bone structure assessed by HR-pQCT, TBS and DXL in adult patients with different types of osteogenesis imperfecta

SummaryBone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) was assessed in adult patients with mild, moderate, and severe osteogenesis imperfecta (OI). The trabecular bone score (TBS), bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA), and dual X-ray and laser (DXL) at the calcaneus were likewise assessed in patients with OI. Trabecular microstructure and BMD in particular were severely altered in patients with OI.IntroductionOI is characterized by high fracture risk but not necessarily by low BMD. The main purpose of this study was to assess bone microarchitecture and BMD at different skeletal sites in different types of OI.MethodsHR-pQCT was performed in 30 patients with OI (mild OI-I, n = 18 (41.8 [34.7, 55.7] years) and moderate to severe OI-III-IV, n = 12 (47.6 [35.3, 58.4] years)) and 30 healthy age-matched controls. TBS, BMD by DXA at the lumbar spine and hip, as well as BMD by DXL at the calcaneus were likewise assessed in patients with OI only.ResultsAt the radius, significantly lower trabecular parameters including BV/TV (p = 0.01 and p < 0.0001, respectively) and trabecular number (p < 0.0001 and p < 0.0001, respectively) as well as an increased inhomogeneity of the trabecular network (p < 0.0001 and p < 0.0001, respectively) were observed in OI-I and OI-III-IV in comparison to the control group. Similar results for trabecular parameters were found at the tibia. Microstructural parameters were worse in OI-III-IV than in OI-I. No significant differences were found in cortical thickness and cortical porosity between the three subgroups at the radius. The cortical thickness of the tibia was thinner in OI-I (p < 0.001), but not OI-III-IV, when compared to controls.ConclusionsTrabecular BMD and trabecular bone microstructure in particular are severely altered in patients with clinical OI-I and OI-III-IV. Low TBS and DXL and their significant associations to HR-pQCT parameters of trabecular bone support this conclusion.

Age- and Sex-Dependent Changes of Intra-articular Cortical and Trabecular Bone Structure and the Effects of Rheumatoid Arthritis.

The objective of this cross‐sectional study was to define normal sex‐ and age‐dependent values of intra‐articular bone mass and microstructures in the metacarpal heads of healthy individuals by high‐resolution peripheral quantitative computed tomography (HR‐pQCT) and test the effect of rheumatoid arthritis (RA) on these parameters. Human cadaveric metacarpal heads were used to exactly define intra‐articular bone. Healthy individuals of different sex and age categories and RA patients with similar age and sex distribution received HR‐pQCT scans of the second metacarpal head and the radius. Total, cortical, and trabecular bone densities as well as microstructural parameters were compared between 1) the different ages and sexes in healthy individuals; 2) between metacarpal heads and the radius; and 3) between healthy individuals and RA patients. The cadaveric study allowed exact definition of the intra‐articular (intracapsular) bone margins. These data were applied in measuring intra‐articular and radial bone parameters in 214 women and men (108 healthy individuals, 106 RA patients). Correlations between intra‐articular and radial bone parameters were good (r = 0.51 to 0.62, p < 0.001). In contrast to radial bone, intra‐articular bone remained stable until age 60 years (between 297 and 312 mg HA/cm3) but decreased significantly (p < 0.001) in women thereafter (237.5 ± 44.3) with loss of both cortical and trabecular bone. Similarly, RA patients showed significant (p < 0.001) loss of intra‐articular total (263.0 ± 44.8), trabecular (171.2 ± 35.6), and cortical bone (610.2 ± 62.0) compared with sex‐ and age‐adjusted controls. Standard sex‐ and age‐dependent values for physiological intra‐articular bone were defined. Postmenopausal state and RA led to significant decrease of intra‐articular bone.

Early Changes of the Cortical Micro-Channel System in the Bare Area of the Joints of Patients With Rheumatoid Arthritis: CoMiC SYSTEM CHANGES IN EARLY RA

To characterize the specific structural properties of the erosion‐prone bare area of the human joint, and to search for early microstructural changes in this region during rheumatoid arthritis (RA).Objective: To characterize the specific structural properties of the erosion-prone bare area of the human joint and to search for early microstructural changes in this region during rheumatoid arthritis Methods: An initial cadaveric study was used for exact localization of the bare area of the metacarpal heads, detection of cortical micro-channels (CoMiCs) in this region by high-resolution peripheral computed tomography (HR-pQCT) and, after anatomical dissection, their validation by micro-computed tomography (μCT). In the second part, number and distribution of CoMiCs were analyzed in 105 healthy individuals and 107 RA patients with similar sex and age distribution. Results: HR-pQCT investigation combined with adaptive thresholding allowed detection of CoMiCs in the bare area of cadaveric joints. Their existence in the bare area was additionally validated by μCT. In healthy individuals, the number of CoMiCs increased with age. RA patients showed significantly (p<0.001) more CoMiCs (112.9±54.7/joint) than healthy individuals (75.2±41.9/joint) with 20-49 years old RA patients exhibiting similar CoMiC numbers as observed in over 65 year old healthy individuals. Importantly, CoMiCs were found in RA patients already very early in their disease course with enrichment in the erosion-prone radial side of the joint. Conclusion: CoMiCs represent a new form of structural change in the joints of patients with RA. While CoMiCs increase with age, RA patients develop such changes much earlier in life and already at the onset of the disease. CoMiCs therefore represent an interesting new opportunity to assess structural changes in RA. This article is protected by copyright. All rights reserved.

Serum Sclerostin Levels Are Decreased in Adult Patients With Different Types of Osteogenesis Imperfecta

CONTEXT There are no specific biochemical bone markers available for osteogenesis imperfecta (OI), and the role of sclerostin as a key regulator of bone formation in OI is unknown. OBJECTIVES We aimed to evaluate the role of sclerostin and its association with bone turnover markers as well as body composition parameters in adult patients with different types of OI. DESIGN, SETTING, AND PARTICIPANTS This was a case-control study in 27 adult patients and 50 healthy age- and gender-matched controls. MAIN OUTCOME MEASURES Serum sclerostin levels and bone turnover markers including serum osteocalcin, amino terminal propeptide of type I procollagen, and CrossLaps as well as body composition parameters were determined in mild OI stage I (OI-I) and moderate-severe OI stages III-IV (OI-III-IV), according to Sillence classification. Data were compared with healthy controls. RESULTS Sclerostin levels were significantly lower in OI-I (19.9 ± 10.9 pmol/L; P < .001) and OI-III-IV (13.3 ± 10.0 pmol/L; P < .001) compared with healthy adults (45.3 ± 14.9 pmol/L), even after adjustment for age, sex, bone mineral content, and body mass index. CrossLaps and PTH were significantly lower in OI-I (0.197 ± 0.15 ng/L; P = .007 and 33.7 ± 19.1 pg/L; P = .033, respectively) and OI-III-IV (0.221 ± 0.18 ng/L; P = .039, and 27.9 ± 14.7 pg/L; P = .001, respectively) than in healthy controls (0.322 ± 0.15 ng/L and 45.0 ± 16.6 pg/L). Amino-terminal propeptide of type I procollagen was below the reference range for OI-I and OI-III-IV. Patients with OI were shorter and lighter and had a decreased bone mineral content (P < .001) but similar fat distribution and lean body mass, compared with controls. Serum sclerostin levels were not related to any bone marker except osteocalcin, the number of prevalent fractures, or body composition readings. CONCLUSION Decreased sclerostin levels in OI might reflect a down-regulation or negative feedback mechanism to prevent further bone loss.

Rheumatoid arthritis is characterized by early changes of the cortical micro-channel (CoMiC) system in the bare area of the joints

To characterize the specific structural properties of the erosion‐prone bare area of the human joint, and to search for early microstructural changes in this region during rheumatoid arthritis (RA).Objective: To characterize the specific structural properties of the erosion-prone bare area of the human joint and to search for early microstructural changes in this region during rheumatoid arthritis Methods: An initial cadaveric study was used for exact localization of the bare area of the metacarpal heads, detection of cortical micro-channels (CoMiCs) in this region by high-resolution peripheral computed tomography (HR-pQCT) and, after anatomical dissection, their validation by micro-computed tomography (μCT). In the second part, number and distribution of CoMiCs were analyzed in 105 healthy individuals and 107 RA patients with similar sex and age distribution. Results: HR-pQCT investigation combined with adaptive thresholding allowed detection of CoMiCs in the bare area of cadaveric joints. Their existence in the bare area was additionally validated by μCT. In healthy individuals, the number of CoMiCs increased with age. RA patients showed significantly (p<0.001) more CoMiCs (112.9±54.7/joint) than healthy individuals (75.2±41.9/joint) with 20-49 years old RA patients exhibiting similar CoMiC numbers as observed in over 65 year old healthy individuals. Importantly, CoMiCs were found in RA patients already very early in their disease course with enrichment in the erosion-prone radial side of the joint. Conclusion: CoMiCs represent a new form of structural change in the joints of patients with RA. While CoMiCs increase with age, RA patients develop such changes much earlier in life and already at the onset of the disease. CoMiCs therefore represent an interesting new opportunity to assess structural changes in RA. This article is protected by copyright. All rights reserved.

Early and Sustained Changes in Bone Metabolism After Severe Burn Injury

CONTEXT Severe burn injury causes a massive stress response, consecutively heightened serum levels of acute phase proteins, cortisol, and catecholamines with accompanying disturbance in calcium metabolism. OBJECTIVE Evaluation of early and prolonged changes of serum bone turnover markers (BTMs) and regulators of bone metabolism. DESIGN Longitudinal observational design. SETTING University clinic. PATIENTS A total of 32 male patients with a median age of 40.5 years and a median burned total body surface area of 40% (83% patients with full thickness burn injury). INTERVENTIONS None. MAIN OUTCOME MEASURES Comparison of changes of BTM/regulators of bone metabolism in the early (d 2–7) and prolonged (d 7–56) phases after trauma. RESULTS All investigated BTM/regulators significantly changed. During the early phase, pronounced increases were observed for serum type 1 collagen cross-linked C-telopeptide, intact N-terminal propeptide of type I procollagen, sclerostin, Dickkopf-1, bone-specific alkaline phosphatase, fibroblast growth factor 23, and intact parathyroid hormone levels, whereas 25-hydroxyvitamin D, albumin, serum, and ionized calcium levels decreased. Changes of osteoprotegerin, osteocalcin, and phosphate were less pronounced but remained significant. In the prolonged phase, changes of intact N-terminal propeptide of type I procollagen were most pronounced, followed by elevated sclerostin, osteocalcin, bone-specific alkaline phosphatase, and lesser changes for albumin levels. Calcium and ionized calcium levels tardily increased and remained within the limit of normal. In contrast, levels of intact parathyroid hormone, fibroblast growth factor 23, C-reactive protein, and to a lesser extent serum type 1 collagen cross-linked C-telopeptide and phosphate levels declined significantly during this phase of investigation. CONCLUSIONS Ongoing changes of BTM and regulators of bone metabolism suggest alterations in bone metabolism with a likely adverse influence on bone quality and structure in male patients with severe burn injuries.

Enhanced Callus Formation After Six Weeks of Parathyroid Hormone Treatment in a Man with Multiple Pelvic Fractures and Osteogenesis Imperfecta Type IV AC ase Report

Osteogenesis imperfecta (OI) is a genetic disorder involving a defect in collagen synthesis1-3. OI is characterized by impaired bone formation, low bone mass, and deterioration of bone architecture in adults4,5. Typical bone features are a decrease in trabecular thickness and number of trabeculae, as well as thin cortices. As a result, there is increased bone fragility with recurrent fractures, leading frequently to skeletal deformities. Currently, no supportive therapy for fracture-healing is available, although preclinical studies show promise for the use of teriparatide (parathyroid hormone [PTH] 1-34)6-9. We present the case of a patient with multiple pelvic fractures and osteogenesis imperfecta type IV who demonstrated enhanced callus formation after treatment with PTH. The patient was informed that data concerning the case would be submitted for publication and he provided consent. A seventy-eight-year-old man with osteogenesis imperfecta (Sillence type IV) was admitted to the hospital with severe pelvic pain following pelvic fractures in five locations (the superior and inferior pubic rami on both the left and right sides and the sacrum), which had been sustained three months earlier after a fall. The initial office visit had been in a specialized trauma center. The patient had been treated with bisphosphonate therapy (alendronate followed by ibandronate) for a minimum of ten years. Since the occurrence of the pelvic fractures, the patient had been confined to a wheelchair and had been dependent on analgesics (tramadol hydrochloride, metamizol, diclofenac) for severe, chronic pain. The earlier fracture history had consisted of numerous nonvertebral fractures after minor trauma in the left radius, right malleolus, right thumb, left femoral neck (followed with total endoprosthesis), ilium, and multiple ribs. The spine had been stabilized from T12 to L2, with posterior lumbar interbody fusion …