Identification of circulating microRNA patterns in patients in psoriasis and psoriatic arthritis.

OBJECTIVE: miRNAs are small non-coding RNAs that control gene expression. Specific intra- and extracellular miRNA signatures have been identified in various diseases. Whether certain miRNA signatures are associated with psoriasis (PsO) and PsA is currently unknown. We aimed to search for circulating miRNA signatures associated with PsO and PsA patients. METHODS: Expression of miRNAs was analysed by reverse transcription quantitative real-time PCR (RT-qPCR) in the serum of PsA, PsO patients and healthy controls. Demographic and disease-specific characteristics and imaging data from hand MRI were recorded. In the discovery phase, 192 miRNA assays were analysed in 48 samples (PsA, PsO, controls: each N = 16). For validation, 17 selected miRNAs were measured in the total population. RESULTS: A total of 141 patients and controls were analysed (51 PsA, 40 PsO, 50 controls). In the discovery phase 51 miRNAs in PsO and 64 miRNAs in PsA were down- or upregulated compared with controls, with 33 miRNAs being changed in both (adj. P < 0.05). The 17 top candidates from discovery were assessed in the validation phase, 9 of them discriminated PsA and PsO from controls [area under the curve (AUC) ≥0.70, all P < 0.05]. Four miRNAs (miR-19b-3p, miR-21-5p, miR-92a-3p and let-7b-5p) were significantly differently regulated between PsO and PsA. A combination of these miRNAs increased the AUC to 0.92 in multivariate regression model to discriminate PsO and PsA. CONCLUSION: miRNA signatures in PsA and PsO patients differ from controls. Nine miRNAs were differentially regulated in PsA and PsO patients, five of them previously reported to be involved in bone and cartilage metabolism, indicating an intimate association of psoriatic inflammation and bone/cartilage changes.

Chondrosarcoma of the spine-a case report.

CASE: A 73-year-old male patient presented with a 3-month history of back pain. In bone scintigraphy and the FDG PET-CT scan (fluorodeoxyglucose positron-emission computed tomography), highly suspect uptake levels were found in TH12-L1. Accordingly, an osteodestructive process was found on MRI (magnetic resonance imaging). Following a successfully performed biopsy of TH12, histologic analysis of the bone material revealed a chondrosarcoma (G1; T4N2M0). Complete resection of the tumor was successfully performed, since chondrosarcoma are resistant to radiation and chemotherapy. CONCLUSION: As chondrosarcoma is a rare bone neoplasm, it must be considered in the differential diagnosis of lower back pain to initiate adequate treatment.

Dispensing anti-osteoporotic drugs changed during the COVID-19 pandemic.

OBJECTIVES: Caring for osteoporosis patients has proven challenging during the COVID-19 pandemic due to repeated lockdowns in Austria. The distinct possibility of insufficient treatment regimens is therefore a matter of pressing concern. The aim of the study was to assess alterations in dispensing anti-osteoporotic drugs during the COVID-19 pandemic. PATIENTS/METHODS: This study was a nationwide retrospective register-based observational study which included all patients in Austria aged ≥50 who received at least one prescription for anti-osteoporotic medication between January 2016 and November 2020. Pseudonymised individual-level patients' data were obtained from social insurance authorities. Anti-osteoporotic agents were divided into: (i) oral bisphosphonates, (ii) intravenous bisphosphonates, (iii) selective estrogen receptor modulators (SERMs), (iv) teriparatide (TPTD) and (v) denosumab (DMAB). We used interrupted time series analysis with autoregressive integrated moving average models (ARIMA) to predict drug dispensing. RESULTS: There were 2,884,374 dispensations of anti-osteoporotic drugs to 224,598 patients between 2016 and 2020. The mean monthly prescriptions for oral bisphosphonates (-14.5 %) and SERMs (-12.9 %) decreased during the COVID-19 pandemic when compared to the non-COVID-19 period. Dispensing for intravenous bisphosphonates (1.7 %) and teriparatide (9.5 %) increased. Prescriptions for DMAB decreased during the first lock-down, however increased by 29.1 % for the total observation time. The Arima models showed that in March 2020 (beginning of the 1st COVID-19 lockdown), there was a decrease of 778 dispensings, with a further increase of 14 dispensings every month for denosumab; a decrease by 178 dispensings, with a further increase of 23 dispensings every month for zolendronic acid; a decrease by 2950 dispensings, but with a further increase of 236 dispensings every other month for ibandronate and a decrease by 1443 dispensing with a further decrease of 29 dispensings for alendronate than predicted, had the lockdown not occurred. CONCLUSIONS: The total number of prescriptions dispensed to patients treated with anti-osteoporotic medications declined rapidly during first COVID-19 lockdown. The observed decrease of DMAB during the first lockdown rebounded in the following months. Considering the massive treatment gap for osteoporosis, and the related fracture risk, clinicians should continue treatment, even during a pandemic.

Fracture patterns in patients with multiple fractures: the probability of multiple fractures and the most frequently associated regions.

INTRODUCTION: Multiple fractures are of high clinical relevance, as a significant increase in mortality rate has been described. The purpose of this study was to evaluate differences in age and gender distribution in multiple fractures dependent on severity of trauma. Furthermore, affected anatomic regions and frequently associated fracture regions were investigated. METHODS: Patients who had sustained multiple fractures between 2000 and 2012 were included in this study. At hospital admission, patients were divided according to trauma severity (high- vs low-traumatic), gender, and age for demographic analysis. Fractures were grouped in anatomical regions, and multiple fracture event probabilities as well as frequently associated regions were calculated. RESULTS: In total, 25,043 patients at an age range of 0-100 years (5.8% of all fracture patients; 14,769 male and 10,274 female patients) who sustained 57,862 multiple fractures were included. The lumbar/thoracic spine, cervical spine, femoral shaft, skull, and pelvis showed a probability of more than 40% of the presence of further fractures in each high-traumatic fracture event. In high-traumatic fracture events, male patients were more affected (p < 0.001). Considering low-traumatic fractures, female patients had a significantly higher proportion (p < 0.001) of multiple fractures among all fractures than male patients. CONCLUSIONS: As a novelty, gender as well as age distributions in multiple fracture patients and a probability statement with the most affected anatomic regions, the risk of presence of further fractures for every region, and the frequently associated fracture regions including the percentage of occurrence are provided. These aspects yield new opportunities for clinical work and may reduce the high rate of overlooked fractures stated in the literature.

Secreted microvesicular miR-31 inhibits osteogenic differentiation of mesenchymal stem cells.

Damage to cells and tissues is one of the driving forces of aging and age-related diseases. Various repair systems are in place to counteract this functional decline. In particular, the property of adult stem cells to self-renew and differentiate is essential for tissue homeostasis and regeneration. However, their functionality declines with age (Rando, 2006). One organ that is notably affected by the reduced differentiation capacity of stem cells with age is the skeleton. Here, we found that circulating microvesicles impact on the osteogenic differentiation capacity of mesenchymal stem cells in a donor-age-dependent way. While searching for factors mediating the inhibitory effect of elderly derived microvesicles on osteogenesis, we identified miR-31 as a crucial component. We demonstrated that miR-31 is present at elevated levels in the plasma of elderly and of osteoporosis patients. As a potential source of its secretion, we identified senescent endothelial cells, which are known to increase during aging in vivo (Erusalimsky, 2009). Endothelial miR-31 is secreted within senescent cell-derived microvesicles and taken up by mesenchymal stem cells where it inhibits osteogenic differentiation by knocking down its target Frizzled-3. Therefore, we suggest that microvesicular miR-31 in the plasma of elderly might play a role in the pathogenesis of age-related impaired bone formation and that miR-31 might be a valuable plasma-based biomarker for aging and for a systemic environment that does not favor cell-based therapies whenever osteogenesis is a limiting factor.

High-resolution Quantitative Computed Tomography Demonstrates Structural Defects in Cortical and Trabecular Bone in IBD Patients.

BACKGROUND AND AIMS: To investigate the macro- and microstructural changes of bone in patients with inflammatory bowel disease [IBD] and to define the factors associated with bone loss in IBD. METHODS: A total of 148 subjects, 59 with Crohn's disease [CD], 39 with ulcerative colitis [UC], and 50 healthy controls were assessed for the geometric, volumetric and microstructural properties of bone using high-resolution peripheral quantitative computed tomography. In addition, demographic and disease-specific characteristics of IBD patients were recorded. RESULTS: IBD patients and controls were comparable in age, sex, and body mass index. Total [p = 0.001], cortical [p < 0.001], and trabecular volumetric bone mineral density [BMD] [p = 0.03] were significantly reduced in IBD patients compared with healthy controls. Geometric and microstructural analysis revealed significantly lower cortical area [p = 0.001] and cortical thickness [p < 0.001] without differences in cortical porosity, pore volume, or pore diameter. CD showed a more severe bone phenotype than UC: cortical bone loss was observed in both diseases, but CD additionally showed profound trabecular bone loss with reduced trabecular BMD [p = 0.008], bone volume [p = 0.008], and trabecular thickness [p = 0.009]. Multivariate regression models identified the diagnosis of CD, female sex, lower body mass index, and the lack of remission as factors independently associated with bone loss in IBD. CONCLUSION: IBD patients develop significant cortical bone loss, impairing bone strength. Trabecular bone loss is limited to CD patients, who exhibit a more severe bone phenotype compared with UC patients.

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.

Atypical Femoral Fractures-Ongoing and History of Bone-Specific Therapy, Concomitant Diseases, Medications, and Survival.

Although atypical femoral fractures (AFFs) are generally rare events; several studies have indicated a potential link between AFF and long-term bone-specific therapies (BSTs). The aim of this study was to analyze the frequency of AFF and potential associations with prior or ongoing BST. A total of 8851 Caucasian female and male patients with de novo hip fractures treated in the largest Austrian level 1 trauma center from 2000 to 2013 were selected. Of the total, 194 patients with a de novo low-traumatic subtrochanteric or shaft fractures were identified: 35 atypical and 159 typical fractures. Of these patients, concomitant diseases, medication, previous fractures, and survival data were retrieved and analyzed. Female patients in both groups were significantly older. The median survival was significantly shorter in patients with AFF (9 vs 18 months; p < 0.0001). Cardiovascular disease, sarcopenia, chronic kidney disease, type 2 diabetes, smoking (past or current history), and prevalent fragility fractures were more frequent in AFF patients, as well as the concomitant use of phenprocoumon, furosemide, and sulfonylurea. Although the number of patients with current BST was less in (14.5%) both groups, more patients in the AFF group were previously treated with BST (71% vs 49%; p = 0.016), and they received these therapies for a longer time period. A combination of severe comorbidities, long-term pharmaceutical therapies, and a history of previous or ongoing BST was associated with an increased individual risk for AFF.

Vitamin D levels and comorbidities in ambulatory and hospitalized patients in Austria.

Vitamin D in its hormonal active form, 1,25-dihydroxyvitamin D (calcitriol), has a major impact on bone turnover by regulating calcium and phosphate homoeostasis. By binding the active vitamin D hormone to the vitamin D receptor (VDR), it acts as a nuclear transcription factor (Bouillon et al., Endocr Rev 29(6):726-776, 2008). The discovery that almost all tissues and cells in the body express the VDR and that several tissues possess the enzymatic capability to convert 25-hydroxyvitamin D (25(OH)-D3; cholecalciferol) to the active form, suggests that vitamin D fulfills various extra-osseous functions (Bouillon et al., Endocr Rev 29(6):726-776, 2008; Holick, N Engl J Med 357(3):266-281, 2007). For example, VDR ensures adequate intestinal calcium absorption by regulating the synthesis of several calcium transport proteins in the duodenum (Bouillon et al., Endocr Rev 29(6):726-776, 2008). Additionally, vitamin D is important for proper muscle function, and some studies suggest it may contribute to prevent type 1 diabetes mellitus, certain autoimmune diseases, hypertension, and several types of cancer (Holick, N Engl J Med 357(3):266-281, 2007).

Quantitative and Qualitative Changes of Bone in Psoriasis and Psoriatic Arthritis Patients.

Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by periarticular bone loss and new bone formation. Current data regarding systemic bone loss and bone mineral density (BMD) in PsA are conflicting. The aim of this study was to evaluate bone microstructure and volumetric BMD (vBMD) in patients with PsA and psoriasis. We performed HR-pQCT scans at the ultradistal and periarticular radius in 50 PsA patients, 30 psoriasis patients, and 70 healthy, age- and sex-related controls assessing trabecular bone volume (BV/TV), trabecular number (Tb.N), inhomogeneity of the trabecular network, cortical thickness (Ct.Th), and cortical porosity (Ct.Po), as well as vBMD. Trabecular BMD (Tb.BMD, p = 0.021, 12.0%), BV/TV (p = 0.020, -11.9%), and Tb.N (p = 0.035, 7.1%) were significantly decreased at the ultradistal radius and the periarticular radius in PsA patients compared to controls. In contrast, bone architecture of the ultradistal radius and periarticular radius was similar in patients with psoriasis and healthy controls. Duration of skin disease was associated with low BV/TV and Tb.N in patients with PsA. These data suggest that trabecular BMD and bone microstructure are decreased in PsA patients. The observation that duration of skin disease determines bone loss in PsA supports the concept of subclinical musculoskeletal disease in psoriasis patients.

[Cathepsin K antagonists: preclinical and clinical data]. / Cathepsin K-Inhibitoren: präklinische und klinische Daten.

Cathepsin K, a cysteine protease, is an essential enzyme in degradation of collagen type I. Since cathepsin K is relatively specific to osteoclasts, it represents a promising candidate for drug development. In the past decades, efforts have been made in developing highly potent, selective and orally applicable cathepsin K inhibitors. In contrast to balicatib and relacatib, whose drug development programmes were stopped due to cutaneous side-effects related to limited drug specificity, the more specific cathepsin K inhibitors odanacatib (ODN) and ONO-5334 have entered clinical trials. Odanacatib progressively increases bone mineral density (BMD) and decreases bone resorption markers in postmenopausal women with low BMD. Its clinical efficacy and safety was confirmed by several clinical studies but indicates that odanacatib is characterized by a resolution-of-effect with increases in bone resorption and rapid decreases in BMD following treatment discontinuation. A phase III fracture prevention study in postmenopausal women with osteoporosis is currently in the final phase.

Sclerostin levels and changes in bone metabolism after bariatric surgery.

CONTEXT: The role of sclerostin as a key regulator of bone formation remains unknown after Roux-en-Y gastric bypass (RYGB) or laparoscopic sleeve gastrectomy (SG). OBJECTIVES: The study objectives were evaluation of sclerostin and Dickkopf-1 (DKK-1) serum levels after surgery and correlations with bone turnover markers (P1NP, CTX), parathyroid hormone (iPTH) and areal bone mineral density (BMD), changes at total body, lumbar spine and total hip. DESIGN AND SETTING: This was a prospective observational single-center two-arm study in premenopausal women with acute adipositas over 24 months. PARTICIPANTS: Participants were 52 premenopausal women (40 ± 8 years, BMI 43.4) after RYGB and 38 premenopausal women (41 ± 7 years, BMI 45.7) after SG. MAIN OUTCOME MEASURES: Prior to surgery and 1, 3, 6, 9, 12, 18, and 24 months after surgery sclerostin, DKK-1, CTX, P1NP levels and BMD were measured. RESULTS: Sclerostin, CTX and (to a lesser extent) P1NP increased after surgery and remained elevated during the entire study period (P < 0.001). DKK-1 declined during months 3-9 (P < 0.005) and then remained unchanged, serum phosphate continuously increased (P < 0.001), iPTH remained within the upper normal limit. Sclerostin increases were significantly positively correlated with CTX and P1NP increases and negatively correlated with BMD loss. BMD independently declined regardless of RYGB and SG. Elevations of sclerostin, CTX, P1NP, and phosphate, but not DKK-1 and iPTH, were significant discriminating factors for BMD loss (AUC 0.920). CONCLUSION: Rapid and sustained increases of sclerostin, CTX, and to a lesser extent, P1NP cause an increase in bone metabolism and result in BMD loss at all skeletal sites.

Intravenous treatment with ibandronate normalizes bone matrix mineralization and reduces cortical porosity after two years in male osteoporosis: a paired biopsy study.

The spectrum of therapeutic options and the amount of clinical trials for male osteoporosis (mOP) is lower than those for postmenopausal osteoporosis. Therefore, we examined the effects of 24 months of ibandronate (IBN) treatment (3 mg/3 mL intravenously every 3 months) on bone material quality in 19 subjects with mOP within an open-label, single-center, prospective phase III study (Eudract number 2006-006692-20). Patients (median age [25th, 75th percentiles] 53.0 [44.5; 57.0] years) were included if they had low bone mineral density (BMD) and/or at least one low trauma fracture and no secondary cause of osteoporosis. The primary endpoint was to evaluate IBN effects on cancellous (Cn.) and cortical (Ct.) bone mineralization density distribution (BMDD) based on quantitative backscattered electron imaging (qBEI) of paired transiliacal bone biopsies (baseline, 24 months). Secondary endpoints included changes in areal bone mineral density (BMD by dual-energy X-ray absorptiometry [DXA]) and serum markers of bone turnover including type I collagen peptides CrossLaps (CTX), procollagen type 1 amino-terminal propeptide (P1NP), and osteocalcin (OC). At baseline, cancellous bone matrix mineralization from mOP was lower than published reference data (mean degree of mineralization Cn.CaMean -1.8%, p < 0.01). IBN treatment increased calcium concentrations versus baseline (Cn.CaMean +2.4%, Ct.CaMean, +3.0% both p < 0.01), and reduced heterogeneity of mineralization (Cn.CaWidth -14%, p = 0.044; Ct.CaWidth, -16%, p = 0.001), leading to cancellous BMDD within normal range. IBN treatment was associated with a decrease in porosity of mineralized cortical tissue (-25%, p = 0.01); increases in BMD at the lumbar spine, the femoral neck, and the total hip (+3.3%, +1.9%, and +5.6%, respectively, p ≤ 0.01); and reductions in CTX (-37.5%), P1NP (-44.4%), and OC (-36.3%, all p < 0.01). Our BMDD findings are in line with the reduction of bone turnover markers and the increase in BMD by IBN in our patients and suggest that the latter mainly reflects the increase in matrix mineralization and the reduction of cortical porosity in this cohort with mOP.

The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension.

CONTEXT: The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) extension is evaluating the long-term efficacy and safety of denosumab for up to 10 years. OBJECTIVE: The objective of the study was to report results from the first 3 years of the extension, representing up to 6 years of denosumab exposure. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, international, open-label study of 4550 women. INTERVENTION: Women from the FREEDOM denosumab group received 3 more years of denosumab for a total of 6 years (long-term) and women from the FREEDOM placebo group received 3 years of denosumab (crossover). MAIN OUTCOME MEASURES: Bone turnover markers (BTMs), bone mineral density (BMD), fracture, and safety data are reported. RESULTS: Reductions in BTMs were maintained (long-term) or achieved rapidly (crossover) after denosumab administration. In the long-term group, BMD further increased for cumulative 6-year gains of 15.2% (lumbar spine) and 7.5% (total hip). During the first 3 years of denosumab treatment, the crossover group had significant gains in lumbar spine (9.4%) and total hip (4.8%) BMD, similar to the long-term group during the 3-year FREEDOM trial. In the long-term group, fracture incidences remained low and below the rates projected for a virtual placebo cohort. In the crossover group, 3-year incidences of new vertebral and nonvertebral fractures were similar to those of the FREEDOM denosumab group. Incidence rates of adverse events did not increase over time. Six participants had events of osteonecrosis of the jaw confirmed by adjudication. One participant had a fracture adjudicated as consistent with atypical femoral fracture. CONCLUSION: Denosumab treatment for 6 years remained well tolerated, maintained reduced bone turnover, and continued to increase BMD. Fracture incidence remained low.

Congress Report: 5th Central and Eastern Europe (CEE) Summit on Osteoporosis in Bratislava, 2-3 December 2011.

Major aims of the 5th Central and Eastern Europe (CEE) Summit on Osteoporosis held in Bratislava, Slovakia, on 2 and 3 December 2011, were to provide participants with state-of-the-art knowledge in the fields of osteoporosis research, diagnosis, and therapy and to evaluate, compare, and discuss the very heterogeneous health care situations and related challenges in the different countries in CEE and elsewhere. The summit was attended by 70 delegates from 15 countries. State-of-the-art lectures given by international authorities on osteoporosis covered a broad spectrum of topics ranging from osteoporosis in the male population, novel therapies in osteoporosis such as cathepsin K and sclerostin inhibitors, and the implementation and use of FRAX® in CEE, to an update on denosumab for the management of osteoporosis. Workshops organized to enable the exchange of individual experiences addressed the importance and current availability of osteology training for physicians and the impact of patient training programs on therapy compliance. Furthermore, the availability of and need for standardized quality controls and therapy guidelines in different CEE countries were discussed. Finally, based on a questionnaire, a very up-to-date analysis of all participating countries regarding incidences of osteoporosis, commonly used diagnostic and therapeutic measures, the number of specialists and specialized hospitals, and differences in the reimbursement situation in the different countries was generated and presented. On the whole, the very authentic contributions and the synergistic exchange of ideas allowed the identification of both positive developments as well as still existing issues and needs in diagnosis and therapy of osteoporosis.

Update on denosumab in postmenopausal osteoporosis--recent clinical data.

Denosumab, a fully human monoclonal antibody against the key osteoclastogenic factor RANK ligand, is currently approved for the treatment of postmenopausal osteoporosis. Denosumab differs from bisphosphonates in many aspects, for example, its ability to act in the extracellular compartment and its likelihood to be distributed throughout the skeleton. In contrast, bisphosphonates have to be internalized by osteoclasts and are mainly located across bone surfaces. This could explain why patients with osteoporosis, who are already treated with bisphosphonates, might experience further benefit when switching to denosumab. Head-to-head studies revealed that transition to denosumab resulted in a greater increase of bone mineral density (BMD) and a greater reduction of bone turnover than did continued alendronate. Additional analyses of the phase 3 FREEDOM trial demonstrated that fracture reduction was particularly high in cortical bone, such as the wrist. In addition, denosumab treatment for a 5- and 8-year period showed sustained reduction in fracture risk, increase in BMD and continued to be well tolerated. The 7-year extension study of FREEDOM and a phase 3 trial evaluating denosumab for the treatment of male osteoporosis are still ongoing and will provide supportive data in the near future.

Fragility fractures in men with idiopathic osteoporosis are associated with undermineralization of the bone matrix without evidence of increased bone turnover.

The pathogenesis of primary osteoporosis in younger individuals is still elusive. An important determinant of the biomechanical competence of bone is its material quality. In this retrospective study we evaluated bone material quality based on quantitative backscattered electron imaging to assess bone mineralization density distribution (BMDD) in bone biopsies of 25 male patients (aged 18-61 years) who sustained fragility fractures but were otherwise healthy. BMDD of cancellous bone was compared with previously established adult reference data. Complementary information was obtained by bone histomorphometry. The histomorphometric results showed a paucity of osteoblasts and osteoclasts on the bone surface in the majority of patients. BMDD revealed a significant shift to lower mineralization densities for cancellous bone values: CaMean (weighted mean Ca content, -5.9%), CaPeak (mode of the BMDD, -5.6%), and CaHigh (portion of fully mineralized bone, -76.8%) were decreased compared to normative reference; CaWidth (heterogeneity in mineralization, +18.5%) and CaLow (portion of low mineralized bone, +68.8; all P < 0.001) were significantly increased. The shift toward lower mineral content in the bone matrix in combination with reduced indices of bone formation and bone resorption suggests an inherent mineralization defect leading to undermineralized bone matrix, which might contribute to the susceptibility to fragility fractures of the patients. The alteration in bone material might be related to osteoblastic dysfunction and seems fundamentally different from that in high bone turnover osteoporosis with a negative bone balance.

Trabecular bone microstructure and local gene expression in iliac crest biopsies of men with idiopathic osteoporosis.

Male idiopathic osteoporosis (MIO) is a metabolic bone disease that is characterized by low bone mass, microstructural alterations, and increased fracture risk in otherwise healthy men. Although the detailed pathophysiology of MIO has yet to be clarified, evidence increasingly suggests an osteoblastic defect as the underlying cause. In this study we tested the hypothesis that the expression profile of certain osteoblastic or osteoblast-related genes (ie, WNT10B, RUNX2, Osterix, Osteocalcin, SOST, RANKL, and OPG) is different in iliac crest biopsies of MIO patients when compared with healthy controls. Furthermore, we investigated the relation of local gene expression characteristics with histomorphometric, microstructural, and clinical features. Following written informed consent and diligent clinical patient characterization, iliac crest biopsies were performed in nine men. While RNA extraction, reverse-transcription, and real-time polymerase chain reactions (PCRs) were performed on one biopsy, a second biopsy of each patient was submitted for histomorphometry and micro-computed tomography (µCT). Age-matched bone samples from forensic autopsies served as controls. MIO patients displayed significantly reduced WNT10B, RUNX2, RANKL, and SOST expression. Performing µCT for the first time in MIO biopsies, we found significant decreases in trabecular number and connectivity density. Trabecular separation was increased significantly, but trabecular thickness was similar in both groups. Histomorphometry revealed decreased BV/TV and osteoid volume and fewer osteoclasts in MIO. By providing evidence for reduced local WNT10B, RUNX2, and RANKL gene expression and histomorphometric low turnover, our data support the osteoblast dysfunction model discussed for MIO. Further, MIO seems to lead to a different microstructural pathology than age-related bone loss.

Effects of denosumab on bone turnover markers in postmenopausal osteoporosis.

Denosumab, a fully human monoclonal antibody to RANKL, decreases bone remodeling, increases bone density, and reduces fracture risk. This study evaluates the time course and determinants of bone turnover marker (BTM) response during denosumab treatment, the percentage of denosumab-treated women with BTMs below the premenopausal reference interval, and the correlations between changes in BTMs and bone mineral density (BMD). The BTM substudy of the Fracture REduction Evaulation of Denosumab in Osteoporosis every 6 Months (FREEDOM) Trial included 160 women randomized to subcutaneous denosumab (60 mg) or placebo injections every 6 months for 3 years. Biochemical markers of bone resorption (serum C-telopeptide of type I collagen [CTX] and tartrate-resistant acid phosphatise [TRACP-5b]) and bone formation (serum procollagen type I N-terminal propeptide [PINP] and bone alkaline phosphatase [BALP]) were measured at baseline and at 1, 6, 12, 24, and 36 months. Decreases in CTX were more rapid and greater than decreases in PINP and BALP. One month after injection, CTX levels in all denosumab-treated subjects decreased to levels below the premenopausal reference interval. CTX values at the end of the dosing period were influenced by baseline CTX values and the dosing interval. The percentage of subjects with CTX below the premenopausal reference interval before each subsequent injection decreased from 79% to 51% during the study. CTX and PINP remained below the premenopausal reference interval at all time points in 46% and 31% denosumab-treated subjects, respectively. With denosumab, but not placebo, there were significant correlations between CTX reduction and BMD increase (r = -0.24 to -0.44). The BTM response pattern with denosumab is unique and should be appreciated by physicians to monitor this treatment effectively.