Reference Intervals for Bone Impact Microindentation in Healthy Adults: A Multi-Centre International Study.

Impact microindentation (IMI) is a novel technique for assessing bone material strength index (BMSi) in vivo, by measuring the depth of a micron-sized, spherical tip into cortical bone that is then indexed to the depth of the tip into a reference material. The aim of this study was to define the reference intervals for men and women by evaluating healthy adults from the United States of America, Europe and Australia. Participants included community-based volunteers and participants drawn from clinical and population-based studies. BMSi was measured on the tibial diaphysis using an OsteoProbe in 479 healthy adults (197 male and 282 female, ages 25 to 98 years) across seven research centres, between 2011 and 2018. Associations between BMSi, age, sex and areal bone mineral density (BMD) were examined following an a posteriori method. Unitless BMSi values ranged from 48 to 101. The mean (± standard deviation) BMSi for men was 84.4 ± 6.9 and for women, 79.0 ± 9.1. Healthy reference intervals for BMSi were identified as 71.0 to 97.9 for men and 59.8 to 95.2 for women. This study provides healthy reference data that can be used to calculate T- and Z-scores for BMSi and assist in determining the utility of BMSi in fracture prediction. These data will be useful for positioning individuals within the population and for identifying those with BMSi at the extremes of the population.

Reconstruction of remodeling units reveals positive effects after 2 and 12 months of romosozumab treatment.

Romosozumab treatment results in a transient early increase in bone formation and sustained decrease in bone resorption. Histomorphometric analyses revealed that the primary bone-forming effect of romosozumab is a transient early stimulation of modeling-based bone formation on cancellous and endocortical surfaces. Furthermore, preclinical studies have demonstrated that romosozumab may affect changes in the remodeling unit, resulting in positive bone balance. To further investigate the effects of romosozumab on bone balance, mo 12 (M12) and mo 2 (M2) (to analyze early effects) unpaired bone biopsies from the FRAME clinical trial were analyzed using remodeling site reconstruction to assess whether positive changes in bone balance on cancellous/endocortical surfaces may contribute to the progressive improvement in bone mass/structure and reduced fracture risk in osteoporotic women at high fracture risk. At M12, bone balance was higher with romosozumab vs placebo on cancellous (+6.1 vs +1.5 µm; P = .012) and endocortical (+5.2 vs -1.7 µm; P = .02) surfaces; higher bone balance was due to lower final erosion depth (40.7 vs 43.7 µm; P = .05) on cancellous surfaces and higher completed wall thickness (50.8 vs 47.5 µm; P = .037) on endocortical surfaces. At M2, the final erosion depth was lower on the endocortical surfaces (42.7 vs 50.7 µm; P = .021) and was slightly lower on the cancellous surfaces (38.5 vs 44.6 µm; P = .11) with romosozumab vs placebo. Sector analysis of early endocortical formative sites revealed higher osteoid thickness (29.9 vs 19.2 µm; P = .005) and mineralized wall thickness (18.3 vs 11.9 µm; P = .004) with romosozumab vs placebo. These evolving bone packets may reflect the early stimulation of bone formation that contributes to the increase in completed wall thickness at M12. These data suggest that romosozumab induces a positive bone balance due to its effects on bone resorption and formation at the level of the remodeling unit, contributing to the positive effects on bone mass, structure, and fracture risk.

Romosozumab treatment has a dual effect on bone, adding new bone and reducing bone loss. In the FRAME clinical trial, romosozumab increased the bone mass and strength and reduced fracture risk in postmenopausal women with osteoporosis. Addition of new bone occurs early in treatment and rapidly on cancellous and endocortical bone surfaces where bone resorption is not ongoing. However, it remains unclear if romosozumab affects bone loss or gain in areas where bone resorption is ongoing (remodeling units), contributing to a further positive bone balance. Here, we examined whether changes at the remodeling unit occur early (2 mo) and/or late (12 mo) in treatment by using bone biopsies from patients treated with romosozumab or placebo in FRAME. At M2, a combination of lower bone resorption and higher bone gain on endocortical surfaces resulted in a positive bone balance with romosozumab vs placebo. At M12, the bone balance was positive with romosozumab vs placebo due to lower bone resorption on cancellous surfaces and greater bone gain on endocortical surfaces. This demonstrates that romosozumab induces a positive bone balance at remodeling units early in treatment, leading to overall gains observed later, contributing to the positive effects of romosozumab on bone mass and structure.

Validation of forearm fracture diagnoses in administrative patient registers.

The validity of forearm fracture diagnoses recorded in five Norwegian hospitals was investigated using image reports and medical records as gold standard. A relatively high completeness and correctness of the diagnoses was found. Algorithms used to define forearm fractures in administrative data should depend on study purpose. PURPOSE: In Norway, forearm fractures are routinely recorded in the Norwegian Patient Registry (NPR). However, these data have not been validated. Data from patient administrative systems (PAS) at hospitals are sent unabridged to NPR. By using data from PAS, we aimed to examine (1) the validity of the forearm fracture diagnoses and (2) the usefulness of washout periods, follow-up codes, and procedure codes to define incident forearm fracture cases. METHODS: This hospital-based validation study included women and men aged ≥ 19 years referred to five hospitals for treatment of a forearm fracture during selected periods in 2015. Administrative data for the ICD-10 forearm fracture code S52 (with all subgroups) in PAS and the medical records were reviewed. X-ray and computed tomography (CT) reports from examinations of forearms were reviewed independently and linked to the data from PAS. Sensitivity and positive predictive values (PPVs) were calculated using image reports and/or review of medical records as gold standard. RESULTS: Among the 8482 reviewed image reports and medical records, 624 patients were identified with an incident forearm fracture during the study period. The sensitivity of PAS registrations was 90.4% (95% CI: 87.8-92.6). The PPV increased from 73.9% (95% CI: 70.6-77.0) in crude data to 90.5% (95% CI: 88.0-92.7) when using a washout period of 6 months. Using procedure codes and follow-up codes in addition to 6-months washout increased the PPV to 94.0%, but the sensitivity fell to 69.0%. CONCLUSION: A relatively high sensitivity of forearm fracture diagnoses was found in PAS. PPV varied depending on the algorithms used to define cases. Choice of algorithm should therefore depend on study purposes. The results give useful measures of forearm fracture diagnoses from administrative patient registers. Depending on local coding practices and treatment pathways, we infer that the findings are relevant to other fracture diagnoses and registers.

Target Values and Daytime Variation of Bone Turnover Markers in Monitoring Osteoporosis Treatment After Fractures.

The serum bone turnover markers (BTM) procollagen type 1 N-terminal propeptide (P1NP) and C-terminal cross-linking telopeptide of type 1 collagen (CTX) are recommended for monitoring adherence and response of antiresorptive drugs (ARD). BTM are elevated about 1 year after fracture and therefore BTM target values are most convenient in ARD treatment follow-up of fracture patients. In this prospective cohort study, we explored the cut-off values of P1NP and CTX showing the best discriminating ability with respect to adherence and treatment effects, reflected in bone mineral density (BMD) changes. Furthermore, we explored the ability of BTM to predict subsequent fractures and BTM variation during daytime in patients using ARD or not. After a fragility fracture, 228 consenting patients (82.2% women) were evaluated for ARD indication and followed for a mean of 4.6 years (SD 0.5 years). BMD was measured at baseline and after 2 years. Serum BTM were measured after 1 or 2 years. The largest area under the curve (AUC) for discrimination of patients taking ARD or not was shown for P1NP <30 µg/L and CTX <0.25 µg/L. AUC for discrimination of patients with >2% gain in BMD (lumbar spine and total hip) was largest at cut-off values for P1NP <30 µg/L and CTX <0.25 µg/L. Higher P1NP was associated with increased fracture risk in patients using ARD (hazard ratio [HR]logP1NP = 15.0; 95% confidence interval [CI] 2.7-83.3), p = 0.002. P1NP and CTX were stable during daytime, except in those patients not taking ARD, where CTX decreased by 21% per hour during daytime. In conclusion, P1NP <30 µg/L and CTX <0.25 µg/L yield the best discrimination between patients taking and not taking ARD and the best prediction of BMD gains after 2 years. Furthermore, higher P1NP is associated with increased fracture risk in patients on ARD. BTM can be measured at any time during the day in patients on ARD. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Modeling-Based Bone Formation After 2 Months of Romosozumab Treatment: Results From the FRAME Clinical Trial.

The bone-forming agent romosozumab is a monoclonal antibody that inhibits sclerostin, leading to increased bone formation and decreased resorption. The highest levels of bone formation markers in human patients are observed in the first 2 months of treatment. Histomorphometric analysis of bone biopsies from the phase 3 FRAME trial (NCT01575834) showed an early significant increase in bone formation with concomitant decreased resorption. Preclinical studies demonstrated that most new bone formation after romosozumab treatment was modeling-based bone formation (MBBF). Here we analyzed bone biopsies from FRAME to assess the effect of 2 months of romosozumab versus placebo on the surface extent of MBBF and remodeling-based bone formation (RBBF). In FRAME, postmenopausal women aged ≥55 years with osteoporosis were randomized 1:1 to 210 mg romosozumab or placebo sc every month for 12 months, followed by 60 mg denosumab sc every 6 months for 12 months. Participants in the bone biopsy substudy received quadruple tetracycline labeling and underwent transiliac biopsies at month 2. A total of 29 biopsies were suitable for histomorphometry. Using fluorescence microscopy, bone formation at cancellous, endocortical, and periosteal envelopes was classified based on the appearance of underlying cement lines as modeling (smooth) or remodeling (scalloped). Data were compared using the Wilcoxon rank-sum test, without multiplicity adjustment. After 2 months, the median percentage of MBBF referent to the total bone surface was significantly increased with romosozumab versus placebo on cancellous (18.0% versus 3.8%; p = 0.005) and endocortical (36.7% versus 3.0%; p = 0.001), but not on periosteal (5.0% versus 2.0%; p = 0.37) surfaces, with no significant difference in the surface extent of RBBF on all three bone surfaces. These data show that stimulation of bone formation in the first 2 months of romosozumab treatment in postmenopausal women with osteoporosis is predominately due to increased MBBF on endocortical and cancellous surfaces. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Treatment of postmenopausal osteoporosis patients with teriparatide for 24 months reverts forming bone quality indices to premenopausal healthy control values.

Postmenopausal osteoporosis (PMOP) therapies are frequently evaluated by bone mineral density (BMD) gains against patients receiving placebo (calcium and vitamin D supplementation, a mild bone turnover-suppressing intervention), which is not equivalent to either healthy or treatment-naive PMOP. The aim of the present observational study was to assess the effects of TPTD treatment in PMOP (20 µg, once daily) at 6 (TPTD 6m; n = 28, age 65 ± 7.3 years), and 24 (TPTD 24m; n = 32, age 67.4 ± 6.15 years) months on bone quality indices at actively forming trabecular surfaces (with fluorescent double labels). Data from the TPTD-treated PMOP patients were compared with those in healthy adult premenopausal women (HC; n = 62, age 40.5 ± 10.6 years), and PMOP receiving placebo (PMOP-PLC; n = 94, age 70.6 ± 4.5 years). Iliac crest biopsies were analyzed by Raman microspectroscopy at three distinct tissue ages: mid-distance between the second label and the bone surface, mid-distance between the two labels, and 1 µm behind the first label. Mineral to matrix ratio (MM), mineral maturity/crystallinity (MMC), tissue water (TW), glycosaminoglycan (GAGs), and pyridinoline (Pyd) content were determined. Outcomes were compared by ANCOVA with subject age and tissue age as covariates, and health status as a fixed factor, followed by Sidak's post-hoc testing (significance assigned to p < 0.05). Both TPTD groups increased MM compared to PMOP-PLC. While TPTD 6m had values similar to HC, TPTD 24m had higher values compared to either HC or TPTD 6m. Both TPTD groups had lower MMC values compared to PMOP-PLC and similar to HC. TPTD 6m patients had higher TW content compared to HC, while TPTD 24m had values similar to HC and lower than either PMOP-PLC or TPTD 6m. Both TPTD groups had lower GAG content compared to HC group, while TPTD 6m had higher values compared to PMOP-PLC. Finally, TPTD 6m patients had higher Pyd content compared to HC and lower compared to PMOP-PLC, while TPTD 24m had lower values compared to PMOP-PLC and TPTD 6m, and similar to HC group. The results of the present study indicate that effects of TPTD on forming trabecular bone quality indices depend on treatment duration. At the recommended length of 24 m, TPTD restores bone mineral and organic matrix quality indices (MMC, TW, Pyd content) to premenopausal healthy (HC) levels.

The peroxisome proliferator-activated receptor (PPAR) alpha agonist fenofibrate maintains bone mass, while the PPAR gamma agonist pioglitazone exaggerates bone loss, in ovariectomized rats.

BACKGROUND: Activation of peroxisome proliferator-activated receptor (PPAR)gamma is associated with bone loss and increased fracture risk, while PPARalpha activation seems to have positive skeletal effects. To further explore these effects we have examined the effect of the PPARalpha agonists fenofibrate and Wyeth 14643, and the PPARgamma agonist pioglitazone, on bone mineral density (BMD), bone architecture and biomechanical strength in ovariectomized rats. METHODS: Fifty-five female Sprague-Dawley rats were assigned to five groups. One group was sham-operated and given vehicle (methylcellulose), the other groups were ovariectomized and given vehicle, fenofibrate, Wyeth 14643 and pioglitazone, respectively, daily for four months. Whole body and femoral BMD were measured by dual X-ray absorptiometry (DXA), and biomechanical testing of femurs, and micro-computed tomography (microCT) of the femoral shaft and head, were performed. RESULTS: Whole body and femoral BMD were significantly higher in sham controls and ovariectomized animals given fenofibrate, compared to ovariectomized controls. Ovariectomized rats given Wyeth 14643, maintained whole body BMD at sham levels, while rats on pioglitazone had lower whole body and femoral BMD, impaired bone quality and less mechanical strength compared to sham and ovariectomized controls. In contrast, cortical volume, trabecular bone volume and thickness, and endocortical volume were maintained at sham levels in rats given fenofibrate. CONCLUSIONS: The PPARalpha agonist fenofibrate, and to a lesser extent the PPARaplha agonist Wyeth 14643, maintained BMD and bone architecture at sham levels, while the PPARgamma agonist pioglitazone exaggerated bone loss and negatively affected bone architecture, in ovariectomized rats.

Cardiovascular and skeletal safety of zoledronic acid in osteoporosis observational, matched cohort study using Danish and Swedish health registries.

BACKGROUND: This observational safety study used national registers to compare the real world cardiovascular and skeletal safety of zoledronic acid (ZA) against oral bisphosphonates (oBP) and untreated population controls. METHODS: Propensity score matched cohort study in Sweden and Denmark. RESULTS: Matched cohort 1 included 8739 ZA users and 25,577 oBP users while matched cohort 2 included 8731 ZA users and 25,924 untreated subjects. In comparison to oBP users, heart failure risk was higher in ZA users, with an adjusted HR (adj) (95%CI) of 1.17 (1.04;1.32) and a higher all-cause mortality (adj HR 1.24 (1.15; 1.34)), however, there was no increased risk of cardiovascular mortality. In the comparison to untreated subjects, ZA users showed a higher risk of atrial fibrillation, adj HR 1.18 (1.05;1.32), arrhythmias adj HR 1.18 (1.06;1.31), and heart failure, adj HR 1.38 (1.24;1.54). Cardiovascular mortality was lower in ZA users (adj HR 0.87 (0.77; 0.98)) and risk of adverse skeletal outcomes was significantly higher, reflecting more severe osteoporosis in these patients. There was no association of cardiovascular risk with increasing exposure time. Sensitivity analyses produced similar findings with no substantial changes in event rates. CONCLUSIONS: We noted an increased risk of heart failure, fractures and death among ZA users compared with oral BP. The risk of cardiovascular and skeletal outcomes was higher in ZA users than in matched population controls, but there was no increase in cardiovascular mortality in ZA users compared to oral BP or untreated controls. Despite propensity score matching, it is not possible to determine with certainty whether the increased risk of cardiovascular outcomes is consistent with a true drug effect or higher baseline risk in patients who begin ZA treatment.

Altered protein levels in bone marrow lesions of hip osteoarthritis: Analysis by proteomics and multiplex immunoassays.

AIM: To assess tissue level changes of proteome and cytokine profiles of subchondral bone in hip osteoarthritis (OA) affected by bone marrow lesions (BMLs). We compared significant protein level differences in osteoarthritic bone with BMLs to control bone without bone marrow lesions. METHODS: Subchondral bone biopsies were taken from femoral heads of end-stage osteoarthritis patients with (BML, n = 21) and without (CON, n = 9) BMLs. Proteins were extracted through a standardized Trizol protocol and used in the subsequent analyses. Angiogenesis and bone markers were assessed using multiplex immunoassays (Luminex). Liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed to detect significant differences in proteome and peptide profiles between BML and CON. RESULTS: Multiplex immunoassays revealed increased tissue contents of vascular endothelial growth factors (VEGF-A/C/D), endothelin-1, angiopoietin-2 and interleukin-6 (IL-6) in bone with BMLs compared to control bone, whereas osteoprotegerin levels were reduced. Mass spectrometry demonstrated pronounced increase in the levels of hemoglobin (73-fold), serum albumin (30-fold), alpha-1-antitrypsin (9-fold), apolipoprotein A1 (4.7-fold), pre-laminin-A/C (3.7-fold) and collagen-alpha1-XII (3-fold) in BMLs, while aggrecan core protein (ACAN) and hyaluronan and proteoglycan link protein 1 (HAPL1) decreased 37- and 29-fold respectively. CONCLUSION: Reduced osteoprotegerin, ACAN and HAPL1 are consistent with osteoclastic activation and high remodeling activity in BMLs. The pronounced increase in angiogenesis markers, hemoglobin and serum albumin support the presence of increased vascularity in subchondral bone affected by BMLs in OA. VEGFs and IL-6 are known nociceptive modulators, and increased levels are in keeping with pain being a clinical feature frequently associated with BMLs.

Zoledronate.

Zoledronate is the most potent and most long-acting bisphosphonate in clinical use, and is administered as an intravenous infusion. Its major uses are in osteoporosis, Paget's disease, and in myeloma and cancers to reduce adverse skeletal related events (SREs). In benign disease, it is a first- or second-line treatment for osteoporosis, achieving anti-fracture efficacy comparable to that of the RANKL blocker, denosumab, over 3 years, and it reduces fracture risk in osteopenic older women. It is the preferred treatment for Paget's disease, achieving higher rates of remissions which are much more prolonged than with any other agent. Some trials have suggested that it reduces mortality, cardiovascular disease and cancer, but these findings are not consistent across all studies. It is nephrotoxic, so should not be given to those with significant renal impairment, and, like other potent anti-resorptive agents, can cause hypocalcemia in patients with severe vitamin D deficiency, which should be corrected before administration. Its most common adverse effect is the acute phase response, seen in 30-40% of patients after their first dose, and much less commonly subsequently. Clinical trials in osteoporosis have not demonstrated increases in osteonecrosis of the jaw or in atypical femoral fractures. Observational databases are currently inadequate to determine whether these problems are increased in zoledronate users. Now available as a generic, zoledronate is a cost-effective agent for fracture prevention and for management of Paget's disease, but wider provision of infusion facilities is important to increase patient access. There is a need to further explore its potential for reducing cancer, cardiovascular disease and mortality, since these effects could be substantially more important than its skeletal actions.

Effects of teriparatide on hip and upper limb fractures in patients with osteoporosis: A systematic review and meta-analysis.

In randomized clinical trials (RCTs) with teriparatide, the number of patients with incident hip fractures was small and insufficiently powered to show statistically significant differences between groups. We, therefore, conducted a systematic review and meta-analysis of the efficacy of teriparatide in the reduction of hip and upper limb fractures in women and men with osteoporosis. A comprehensive search of databases until 22 November 2017 was conducted for RCTs of at least 6-month duration that reported non-spine fractures (hip, humerus, forearm, wrist), either as an efficacy or safety endpoint. Only RCTs that included patients with the approved treatment indications and dose for use of teriparatide were included; trials with off-label use of teriparatide were excluded. Two independent reviewers performed study selection and data extraction. Statistical procedures included Peto's method and Mantel-Haenszel with empirical correction, as most of the RCTs reported zero events in at least one of the treatment arms. Study results are expressed as odds ratios (OR) with 95% confidence intervals (CI). Publication bias and heterogeneity were evaluated with standard statistical tests. Twenty-three RCTs were included, 19 with an active-controlled arm (representing 64.9% of the patients included in the control group) and 11 double-blind, representing data on 8644 subjects, 3893 of them treated with teriparatide. Mean age (SD) was 67.0 (4.5) years, median treatment duration 18 months (range: 6 to 24 months). A total of 34 incident hip, 31 humerus, 31 forearm, and 62 wrist fractures were included. Meta-analysis results showed an OR (95% CI) for hip fractures of 0.44 (0.22-0.87; p = 0.019) in patients treated with teriparatide compared with controls. The effects on the risk of humerus [1.02 (0.50-2.08)], forearm [0.53 (0.26-1.08)] and wrist fractures [1.21 (0.72-2.04)] were not statistically significant (p > 0.05). This meta-analysis provides evidence of efficacy of teriparatide in reducing hip fractures by 56% in patients with osteoporosis.

Adding Marrow Adiposity and Cortical Porosity to Femoral Neck Areal Bone Mineral Density Improves the Discrimination of Women With Nonvertebral Fractures From Controls.

Advancing age is accompanied by a reduction in bone formation and remodeling imbalance, which produces microstructural deterioration. This may be partly caused by a diversion of mesenchymal cells towards adipocytes rather than osteoblast lineage cells. We hypothesized that microstructural deterioration would be associated with an increased marrow adiposity, and each of these traits would be independently associated with nonvertebral fractures and improve discrimination of women with fractures from controls over that achieved by femoral neck (FN) areal bone mineral density (aBMD) alone. The marrow adiposity and bone microstructure were quantified from HR-pQCT images of the distal tibia and distal radius in 77 women aged 40 to 70 years with a recent nonvertebral fracture and 226 controls in Melbourne, Australia. Marrow fat measurement from HR-pQCT images was validated using direct histologic measurement as the gold standard, at the distal radius of 15 sheep, with an agreement (R2 = 0.86, p < 0.0001). Each SD higher distal tibia marrow adiposity was associated with 0.33 SD higher cortical porosity, and 0.60 SD fewer, 0.24 SD thinner, and 0.72 SD more-separated trabeculae (all p < 0.05). Adjusted for age and FN aBMD, odds ratios (ORs) (95% CI) for fracture per SD higher marrow adiposity and cortical porosity were OR, 3.39 (95% CI, 2.14 to 5.38) and OR, 1.79 (95% CI, 1.14 to 2.80), respectively. Discrimination of women with fracture from controls improved when cortical porosity was added to FN aBMD and age (area under the receiver-operating characteristic curve [AUC] 0.778 versus 0.751, p = 0.006) or marrow adiposity was added to FN aBMD and age (AUC 0.825 versus 0.751, p = 0.002). The model including FN aBMD, age, cortical porosity, trabecular thickness, and marrow adiposity had an AUC = 0.888. Results were similar for the distal radius. Whether marrow adiposity and cortical porosity indices improve the identification of women at risk for fractures requires validation in prospective studies. © 2019 American Society for Bone and Mineral Research.

Post-fracture Risk Assessment: Target the Centrally Sited Fractures First! A Substudy of NoFRACT.

The location of osteoporotic fragility fractures adds crucial information to post-fracture risk estimation. Triaging patients according to fracture site for secondary fracture prevention can therefore be of interest to prioritize patients considering the high imminent fracture risk. The objectives of this cross-sectional study were therefore to explore potential differences between central (vertebral, hip, proximal humerus, pelvis) and peripheral (forearm, ankle, other) fractures. This substudy of the Norwegian Capture the Fracture Initiative (NoFRACT) included 495 women and 119 men ≥50 years with fragility fractures. They had bone mineral density (BMD) of the femoral neck, total hip, and lumbar spine assessed using dual-energy X-ray absorptiometry (DXA), trabecular bone score (TBS) calculated, concomitantly vertebral fracture assessment (VFA) with semiquantitative grading of vertebral fractures (SQ1-SQ3), and a questionnaire concerning risk factors for fractures was answered. Patients with central fractures exhibited lower BMD of the femoral neck (765 versus 827 mg/cm2 ), total hip (800 versus 876 mg/cm2 ), and lumbar spine (1024 versus 1062 mg/cm2 ); lower mean TBS (1.24 versus 1.28); and a higher proportion of SQ1-SQ3 fractures (52.0% versus 27.7%), SQ2-SQ3 fractures (36.8% versus 13.4%), and SQ3 fractures (21.5% versus 2.2%) than patients with peripheral fractures (all p < 0.05). All analyses were adjusted for sex, age, and body mass index (BMI); and the analyses of TBS and SQ1-SQ3 fracture prevalence was additionally adjusted for BMD). In conclusion, patients with central fragility fractures revealed lower femoral neck BMD, lower TBS, and higher prevalence of vertebral fractures on VFA than the patients with peripheral fractures. This suggests that patients with central fragility fractures exhibit more severe deterioration of bone structure, translating into a higher risk of subsequent fragility fractures and therefore they should get the highest priority in secondary fracture prevention, although attention to peripheral fractures should still not be diminished. © 2019 American Society for Bone and Mineral Research. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

High prevalence of vertebral fractures and low trabecular bone score in patients with fragility fractures: A cross-sectional sub-study of NoFRACT.

PURPOSE: Norway has among the highest incidence rates of fractures in the world. Vertebral fracture assessment (VFA) and trabecular bone score (TBS) provide information about fracture risk, but their importance have not been studied in Norwegian patients with fragility fractures. The objectives of this study were to examine the clinical characteristics of a cohort of women and men with fragility fractures, their prevalence of vertebral fractures using VFA and prevalence of low TBS, and explore the differences between the sexes and patients with and without vertebral fractures. METHODS: This cross-sectional sub-study of the Norwegian Capture the Fracture Initiative (NoFRACT) included 839 patients with fragility fractures. Of these, 804 patients had bone mineral density (BMD) of the total hip, femoral neck and/or spine assessed using dual energy x-ray absorptiometry, 679 underwent concomitant VFA, 771 had TBS calculated and 696 responded to a questionnaire. RESULTS: Mean age was 65.8 (SD 8.8) years and 80.5% were women. VFA revealed vertebral fractures in 34.8% of the patients and 34.0% had low TBS (≤ 1.23), with no differences between the sexes. In all patients with valid measures of both VFA and TBS, 53.8% had either vertebral fractures, low TBS, or both. In the patients with osteopenia at the femoral neck, 53.6% had either vertebral fractures, low TBS, or both. Femoral neck BMD T-score ≤ -2.5 was found in 13.8% of all patients, whereas the corresponding figure was 27.4% using the skeletal site with lowest T-score. Women exhibited lower BMD at all sites and lower TBS than men (1.27 vs. 1.29), (all p < 0.05). Patients with prevalent vertebral fractures were older (69.4 vs. 64.0 years), exhibited lower BMD at all sites and lower TBS (1.25 vs.1.29) than those without vertebral fractures (all p < 0.05). Before assessment, 8.2% were taking anti-osteoporotic drugs (AOD), and after assessment, the prescription rate increased to 56.2%. CONCLUSIONS: More than half of the patients with fragility fractures had vertebral fractures, low TBS or both. The prescription of AOD increased seven fold from before assessment to after assessment, emphasizing the importance of risk assessment after a fragility fracture.

Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure.

UNLABELLED: In a substudy of the HORIZON pivotal fracture trial, in which yearly intravenous zoledronic acid 5 mg was found to significantly reduce risk of various fracture types in patients with postmenopausal osteoporosis, 152 patients underwent bone biopsy. Zoledronic acid reduced bone turnover by 63% and preserved bone structure and volume, with evidence of ongoing bone remodeling in 99% of biopsies obtained. INTRODUCTION: In the HORIZON pivotal fracture trial (PFT), enrolling 7,736 women with postmenopausal osteoporosis, three annual intravenous infusions of the bisphosphonate zoledronic acid (5 mg) significantly reduced morphometric vertebral, clinical vertebral, hip, and nonvertebral fractures by 70%, 77%, 41%, and 25%, respectively. Whereas 79% of patients received zoledronic acid/placebo only (stratum I, n = 6,113), 21% received concomitant treatment with other antiresorptive drugs, excluding other bisphosphonates, PTH, and strontium (stratum II, n = 1,652). MATERIALS AND METHODS: To determine effects on bone remodeling and bone architecture, iliac crest bone biopsies were obtained in 152 patients on active treatment or placebo at 3 yr after double tetracycline labeling. In five patients, only qualitative histology was performed, leaving 147 biopsy cores (79 on active treatment and 68 on placebo) for microCT analysis and histomorphometry. RESULTS: Analysis of bone structure by microCT revealed higher trabecular bone volume (BV/TV) in the zoledronic acid group (median, 16.6% versus 12.8%; p = 0.020). In addition, patients treated with zoledronic acid exhibited higher trabecular numbers (p = 0.008), decreased trabecular separation (p = 0.011), and a trend toward improvement in connectivity density (p = 0.062), all indicating better preservation of trabecular structure after treatment with zoledronic acid. Qualitative analysis revealed presence of tetracycline label in 81 of 82 biopsies from patients on zoledronic acid and all 70 biopsies from placebo patients, indicative of continued bone remodeling. No bone pathology was observed. Zoledronic acid induced a 63% median (71% mean) reduction of the activation frequency (Ac.f; p < 0.0001) and reduced mineralizing surface (MS/BS; p < 0.0001) and volume referent bone formation rate (BFR/BV) versus placebo, indicating reduced bone turnover. Mineral appositional rate was higher in the zoledronic acid group (p = 0.0002), suggesting improved osteoblast function compared with placebo. Mineralization lag time was similar in the two groups, whereas osteoid volume (OV/BV; p < 0.0001) and osteoid thickness (O.Th; p = 0.0094) were lower in zoledronic acid-treated patients, indicating normal osteoid formation and mineralization of newly formed bone. Concomitant administration of other antiresorptive osteoporosis therapies (e.g., raloxifene, tamoxifen, tibolone, ipriflavone) did not significantly alter the tissue level response to zoledronic acid. CONCLUSIONS: Annual dosing for 3 yr with zoledronic acid 5 mg intravenously resulted in a median 63% (mean, 71%) reduction of bone turnover and preservation of bone structure and mass without any signs of adynamic bone. Concomitant treatment with other osteoporosis therapies did not significantly affect the bone response to zoledronic acid.

Renal safety of annual zoledronic acid infusions in osteoporotic postmenopausal women.

Intravenous bisphosphonates reduce fracture risk but have been associated in rare cases with deteriorating renal-function in cancer patients. The renal effects of zoledronic acid were assessed in osteoporotic postmenopausal women from 27 countries who received three annual infusions of zoledronic acid or a placebo in a randomized, double-blind trial. Serum creatinine, estimated creatinine clearance and urinary protein were measured before and after at least one infusion in a predefined renal safety cohort of 5035 equally divided patients. This group was compared to 7714 patients whose parameters were measured annually. Significantly more transient pre- to post-infusion increases in serum creatinine occurred in zoledronic acid than placebo-treated patients with significant elevations, relative to pre-infusion, only in the second year. All 31 zoledronic acid and 8 of 10 patients on placebo recovered their pre-infusion serum creatinine value within 12 months. No differences in mean changes in serum creatinine, estimated creatinine clearance or adverse renal events were found. We found that transient changes in renal function can occur following an annual zoledronic acid infusion but, in the long term, renal function was not different from control patients.

Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the health outcomes and reduced incidence with zoledronic acid once yearly pivotal fracture trial.

BACKGROUND: The authors determined incidence of osteonecrosis of the jaw (ONJ) in a large, prospective three-year clinical trial of zoledronic acid in women with postmenopausal osteoporosis (PMO). METHODS: A total of 7,714 women with PMO received intravenous zoledronic acid 5 mg or a placebo. No spontaneous reports of ONJ were received. An independent, blinded adjudication committee searched the trial's adverse event database by using 60 terms. On an ongoing basis, the committee reviewed the identified events, and it defined ONJ as exposed bone in the maxillofacial area with delayed healing for more than six weeks despite appropriate care. RESULTS: One participant who received a placebo and one participant who received zoledronic acid experienced delayed healing associated with infection. Both conditions resolved after antibiotic therapy, débridement or both. CONCLUSION: The occurrence of ONJ is rare in a PMO population, and delayed healing of lesions can occur with and without bisphosphonate use over three years. CLINICAL IMPLICATIONS: The low incidence of ONJ must be assessed in the context of the clinical benefit of zoledronic acid therapy in reducing hip, vertebral and nonvertebral fractures in this at-risk population. There is no evidence to suggest that healthy patients with osteoporosis who are receiving bisphosphonates require any special treatment beyond routine dental care or to support altering standard treatment practices.

Teriparatide Treatment Increases Mineral Content and Volume in Cortical and Trabecular Bone of Iliac Crest: A Comparison of Infrared Imaging With X-Ray-Based Bone Assessment Techniques.

Teriparatide increases bone mass primarily through remodeling of older or damaged bone and abundant replacement with new mineralizing bone. This post hoc analysis investigated whether dual-energy X-ray absorptiometric (DXA) areal bone mineral density (aBMD) measurement adequately reflects changes of mineral and organic matrix content in cortical and trabecular bone. Paired biopsies and aBMD measurements were obtained before and at end of 2 years of teriparatide treatment from postmenopausal women with osteoporosis who were either alendronate pretreated (mean, 57.5 months) or osteoporosis-treatment naive. Biopsies were assessed by micro-computed tomography (µCT) to calculate mean cortical width (Ct.Wi), cortical area (Ct.Ar), and trabecular bone volume fraction (BV/TV). Fourier transformed infrared imaging (pixel size ∼6.3 × 6.3 µm2 ) was utilized to calculate mineral and organic matrix density (mean absorption/pixel), as well as total mineral and organic contents of cortical and cancellous compartments (sum of all pixels in the compartment). Effect of pretreatment over time was analyzed using mixed model repeated measures. µCT derived Ct.Wi and BV/TV increased, accompanied by similar increases in the overall mineral contents of their respective bone compartments. Mineral density did not change. Marked increases in the total content of both mineral and organic matrix associated with volumetric growth in both compartments consistently exceeded those of aBMD. Increases in organic matrix exceeded increases in mineral content in both cortical and trabecular compartments. For percent changes, only change in Ct.Wi correlated to change in femoral neck aBMD (r = .38, p = 0.043), whereas no other significant correlations of Ct.Wi or BV/TV with lumbar spine, total hip, or femoral neck aBMD were demonstrable. These data indicate that 2 years of teriparatide treatment leads to an increased bone organic matrix and mineral content in the iliac crest. The magnitude of these increases in the iliac crest were not detected with conventional aBMD measurements at other skeletal sites. © 2018 American Society for Bone and Mineral Research.

Effect of a Fracture Liaison Service on the Rate of Subsequent Fracture Among Patients With a Fragility Fracture in the Norwegian Capture the Fracture Initiative (NoFRACT): A Trial Protocol.

Importance: Fragility fracture is a major health issue because of the accompanying morbidity, mortality, and financial cost. Despite the high cost to society and personal cost to affected individuals, secondary fracture prevention is suboptimal in Norway, mainly because most patients with osteoporotic fractures do not receive treatment with antiosteoporotic drugs after fracture repair. Objectives: To improve secondary fracture prevention by introducing a standardized intervention program and to investigate the effect of the program on the rate of subsequent fractures. Design, Setting, and Participants: Trial protocol of the Norwegian Capture the Fracture Initiative (NoFRACT), an ongoing, stepped wedge cluster randomized clinical trial in 7 hospitals in Norway. The participating hospitals were cluster randomized to an intervention starting date: May 1, 2015; September 1, 2015; and January 1, 2016. Follow-up is through December 31, 2019. The outcome data were merged from national registries of women and men 50 years and older with a recent fragility fracture treated at 1 of the 7 hospitals. Discussion: The NoFRACT trial is intended to enroll 82 000 patients (intervention period, 26 000 patients; control period, 56 000 patients), of whom 23 578 are currently enrolled by January 2018. Interventions include a standardized program for identification, assessment, and treatment of osteoporosis in patients with a fragility fracture that is led by a trained coordinating nurse. The primary outcome is rate of subsequent fracture (per 10 000 person-years) based on national registry data. Outcomes before (2008-2015; control period) and after (2015-2019; intervention period) the intervention will be compared, and each hospital will act as its own control. Use of outcomes from national registry data means that all patients are included in the analysis regardless of whether they are exposed to the intervention (intention to treat). A sensitivity analysis with a transition window will be performed to mitigate possible within-cluster contamination. Results: Results are planned to be disseminated through publications in peer-reviewed journals and presented at local, national, and international conferences. Conclusions: By introducing a standardized intervention program for assessment and treatment of osteoporosis in patients with fragility fractures, we expect to document reduced rates of subsequent fractures and fracture-related mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT02536898.

Women with type 2 diabetes mellitus have lower cortical porosity of the proximal femoral shaft using low-resolution CT than nondiabetic women, and increasing glucose is associated with reduced cortical porosity.

Increased cortical porosity has been suggested as a possible factor increasing fracture propensity in patients with type 2 diabetes mellitus (T2DM). This is a paradox because cortical porosity is generally associated with high bone turnover, while bone turnover is reduced in patients with T2DM. We therefore wanted to test the hypothesis that women with T2DM have lower bone turnover markers (BTM) and lower cortical porosity than those without diabetes, and that higher serum glucose and body mass index (BMI) are associated with lower BTM, and with lower cortical porosity. This cross-sectional study is based on a prior nested case-control study including 443 postmenopausal women aged 54-94years from the Tromsø Study, 211 with non-vertebral fracture and 232 fracture-free controls. Of those 443 participants, 22 women exhibited T2DM and 421 women did not have diabetes. All had fasting blood samples assayed for procollagen type I N-terminal propeptide (PINP), C-terminal cross-linking telopeptide of type I collagen (CTX) and glucose, and femoral subtrochanteric architecture was quantified using low-resolution clinical CT and StrAx1.0 software. Women with T2DM had higher serum glucose (7.2 vs. 5.3mmol/L), BMI (29.0 vs. 26.4kg/m2), and higher femoral subtrochanteric total volumetric bone mineral density (vBMD) (783 vs. 715mgHA/cm3), but lower cortical porosity (40.9 vs. 42.8%) than nondiabetic women (all p<0.05). Each standard deviation (SD) increment in glucose was associated with 0.10-0.12 SD lower PINP and CTX, and 0.13 SD lower cortical porosity (all p<0.05). Each SD increment in BMI was associated with 0.10-0.18 SD lower serum PINP and CTX, and 0.19 SD thicker cortices (all p<0.05). Increasing glucose and BMI were associated with lower bone turnover suggesting that reduced intracortical and endocortical remodeling leads to reduced porosity and thicker cortices. Using low-resolution clinical CT, cortical porosity was lower in women with T2DM compared to women without diabetes. This indicates that other changes in bone qualities, not increased cortical porosity, are likely to explain the increased fracture propensity in patients with T2DM.