Elevated Bone Hardness Under Denosumab Treatment, With Persisting Lower Osteocyte Viability During Discontinuation.

Denosumab is a potent osteoclast inhibitor targeted to prevent osteoporotic bone loss and thereby reduce fractures in the aging population. Recently, an elevated risk of rebound fractures following denosumab discontinuation was identified, unless patients were transitioned to an alternative antiresorptive medication. How denosumab affects the interaction of mechanosensitive osteocytes and bone quality remains unknown. We hypothesized that denosumab influences osteocyte function contributing to bone reorganization and increased fractures during discontinuation. Bone quality and osteocytes were assessed in archived iliac crest bone biopsies obtained from patients with high fracture occurrence from 2011 to 2016. Biopsies were obtained due to high fracture occurrence prior and during osteoporosis therapy from (i) patients with at least two semiannual subcutaneous injections of 60 mg denosumab, (ii) patients with rebound fractures during discontinuation, and (iii) patients of a treatment-naive group. In total, biopsies from 43 individuals were analyzed (mean age, 65.5 ± 12.1 years). Our results showed that during denosumab treatment, iliac cortical bone had a higher bone tissue hardness compared to treatment-naive bone (p = 0.0077) and a higher percentage of mineralized osteocyte lacunae (p = 0.0095). The density of empty osteocyte lacunae was higher with denosumab compared to treatment-naive (p = 0.014) and remained high in trabecular bone during discontinuation (p = 0.0071). We conclude that during denosumab treatment, increased bone hardness may contribute to improved fracture resistance. In biopsies from patients with high fracture occurrence, denosumab treatment reduced osteocyte viability, an effect that persisted during treatment discontinuation. High-resolution imaging of osteocyte viability indicates a role for osteocytes as a potential future mechanistic target to understand rebound bone loss and increased fractures with denosumab discontinuation.

CT- and ultrasound-characteristics of hepatic lesions in patients with multiple endocrine neoplasia syndrome. A retrospective image review of 25 cases.

INTRODUCTION: Liver metastases from neuroendocrine tumors in multiple endocrine neoplasia syndrome are common (75%) and significantly impairs the prognosis. Characterisation of liver lesions in these patients is challenging, as liver metastases are difficult to differentiate from benign liver lesions such as haemangioma. METHODS: In this study we aimed to characterize the radiological findings of hepatic metastases in MEN patients. The findings of contrast-enhanced CT were considered for the main diagnosis. We retrospectively evaluated 25 patients with MEN-syndrome (10 MEN1/ 15 MEN2) including 11 men and 14 women between 28-62 years of age. RESULTS: Liver metastases (48%, 12/25) and hemangioma (40%, 10/25) were the most common liver lesions among our patients. The most common primary tumors in our MEN1 and MEN2 patients with liver metastases were of pancreatic neuroendocrine tumor (70%, 7/10) und medullary thyroid carcinoma (100%, 15/15) origin, respectively. CT-characteristics were grouped into three main categories, depending on contrast dynamics. The majority of hepatic metastases (75%, 14/25) are presented as multiple lesions with a slow growth in an average 5 years of follow-up-period. We were able to find a common CT pattern and categorise these for each MEN-syndrome. Hepatic metastases in MEN1 presented commonly a blurred arterial enhancement with a low portal venous enhancement and less frequently a prominent enhancement in the arterial phase, which mimics the classical haemangioma. In MEN2 the liver metastases exhibited disseminated mixed hyper- and hypo-enhanced lesions in CT-scans. Moreover, lesion calcifications are pathognomonic in MEN2. The main limitation of this study is the missing histopathological confirmation in the majority of cases. CONCLUSIONS: In this retrospective imaging study, we were able to categorise and find a common CT pattern for hepatic lesions in patients with MEN-syndrome. In order to differentiate these lesions sufficiently, a combination of a 3-phasic CT-scan with US is required. Other liver specific imaging modalities (MRI, CEUS, SMS-PET/CT) should complement the diagnosis in individual cases.

Setbacks in Alzheimer research demand new strategies, not surrender.

In this month's editorial, the PLOS Medicine Editors discuss the challenges of addressing a growing population with Alzheimer disease and dementia amidst disappointing news from the pharmaceutical industry.

From radiation osteitis to osteoradionecrosis: incidence and MR morphology of radiation-induced sacral pathologies following pelvic radiotherapy.

OBJECTIVE: To investigate the incidence rate, time-to-onset and recovery, MRI morphology and occurrence of insufficiency fractures in radiation-induced changes in the sacrum following pelvic radiotherapy. MATERIAL AND METHODS: 410 patients with pelvic malignancies treated with radiotherapy were reviewed. Follow-up was 1-124 months (mean 22 months). Serial MRI (average four studies/patient) were analysed using a new semi-quantitative score (Radiation-Induced Sacral Changes=RISC). A size category (I/II/III), a type category for MR signal morphologies (a/b/c) and sacral insufficiency fractures (+/-) were applied. RESULTS: Seventy-two patients (17.6 %) were found to have new pathological signal changes. Radiation osteitis was documented in 83.3 % (60/72, RISC stage a + b), and definite osteonecrosis (stage c) in 12 patients (16.7 %, 12/72). Thirty-one patients (43.1 %) had sacral insufficiency fractures. Initial bone marrow signal changes were found 1-35 months (median 4 months) after radiotherapy. The maximum manifestation of radiation-induced signal changes occurred after 1-35 months (mean 11 months). Fifty-six cases (77.8 %) showed a significant signal recovery within 16.5 months. CONCLUSION: Radiation-induced bone marrow changes appear with a high incidence at the sacrum with an early onset and frequent recovery. The majority presented a pattern of radiation osteitis, whereas osteoradionecrosis was proportionately rare. KEY POINTS: • Radiation-induced sacral bone marrow changes appear frequently (17.6 %) following pelvic radiotherapy. • Insufficiency fractures are common late effects (43 %). • Radiation osteitis develops early (4 mo), with recovery between 16.5 and 39.5 months. • Definite radiological osteoradionecrosis is proportionately rare (3 %). • A 3-stage classification system simplifies and standardizes the morphological disease staging.

Predictive value of MRI features for development of radiographic osteoarthritis in a cohort of participants with pre-radiographic knee osteoarthritis-the CHECK study.

OBJECTIVE: To determine whether MRI features are associated with development of radiographic knee OA and can be used as a predictive tool in early knee OA. METHODS: In 148 participants of the Cohort Hip and Cohort Knee study (mean age 56 years, 78% women), with a Kellgren Lawrence (KL) score ⩽1, we obtained semi-quantitatively scored knee MRI scans and radiographs at baseline. After 5 years, we determined the development of radiographic knee OA (KL ⩾2). We calculated odds ratios (ORs), with 95% CIs adjusted for age, sex and BMI, to identify MRI features associated with OA development. With these MRI features, we constructed an internally validated prediction model, for which we measured the area under the receiver operating characteristics curve, sensitivity and specificity. RESULTS: Radiographic OA developed in 28% of the participants after 5 years. Statistically significant associations were: cartilage defects OR = 1.7 (95% CI: 1.1, 2.6), osteophytes OR = 3.1 (1.7, 5.7), bone marrow lesions OR = 2.0 (1.2, 3.4), effusion OR = 2.1 (1.2, 3.5) and meniscal pathology OR = 2.8 (1.3, 6.3). With the combined MRI features in a prediction model, the sensitivity was 66%, the specificity 67% and the optimism-corrected area under the receiver operating characteristics curve 0.685. CONCLUSION: In early knee OA, MRI depicts significantly associated pathology in cartilage, bone and menisci, whereas the radiograph fails to detect these changes. Although MRI has potential for identifying patients at risk for developing radiographic knee OA, it cannot be used as an absolute diagnostic tool in early knee OA due to its low discriminative ability.

Potential of quantitative susceptibility mapping for detection of prostatic calcifications.

PURPOSE: To evaluate whether quantitative susceptibility (QSM) may be used as an alternative to computed tomography (CT) to detect calcification in prostate cancer patients. MATERIALS AND METHODS: Susceptibility map calculation was performed using 3D gradient echo magnetic resonance imaging (MRI) data from 26 patients measured at 3T who previously received a planning CT of the prostate. Phase images were unwrapped using Laplacian-based phase unwrapping, the background field was removed with the V-SHARP method, and susceptibility maps were calculated with the iLSQR method. Two blinded readers were asked to identify peri- and intraprostatic calcifications. RESULTS: Average mean and minimum susceptibility values (referenced to iliopsoas muscle) of calcifications were -0.249 ± 0.179 ppm and -0.551 ± 0.323 ppm, and average mean and maximum intensities in CT images were 319 ± 164 HU and 679 ± 392 HU. Twenty-one and 17 out of 22 prostatic calcifications were identified using susceptibility maps and magnitude images, respectively, as well as more than half of periprostatic phleboliths depicted by CT. Calcifications in the prostate and its periphery were quantitatively differentiable from noncalcified prostate tissue in CT (mean values for calcifications / for noncalcified tissue: 71 to 649 / -1 to 83 HU) and in QSM (mean values for calcifications / for noncalcified tissue: -0.641 to 0.063 / -0.046 to 0.181 ppm). Moreover, there was a significant correlation between susceptibility values and CT image intensities for calcifications (P < 0.004). CONCLUSION: Prostatic calcifications could be well identified with QSM. Susceptibility maps can be easily obtained from clinical prostate MR protocols that include a 3D gradient echo sequence, rendering it a promising technique for detection and quantification of intraprostatic calcifications. LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:889-898.

Histological response assessment following neoadjuvant isolated limb perfusion in patients with primary, localised, high-grade soft tissue sarcoma.

PURPOSE: Histological response assessment following neoadjuvant treatment can help identify patients at a higher risk for systemic disease progression. Our goal was to evaluate whether mitotic count and the amount of viable tumour following neoadjuvant isolated limb perfusion (ILP) for primary, locally advanced, non-metastatic, high-grade extremity soft tissue sarcoma correlate with prognosis. PATIENTS AND METHODS: This study is a retrospective analysis of 61 patients who underwent neoadjuvant ILP followed by surgical resection with curative intent between 2001 and 2011. Non-parametric analyses were carried out with the Mann-Whitney U and the Wilcoxon signed-rank test. Survival curves were calculated with the Kaplan-Meier method and compared with the log-rank test. RESULTS: The median follow-up was 44 months for all patients and 55 months for survivors. The amount of viable tumour after ILP had no correlation with overall (OS) (P = 0.227) or event-free (EFS) (P = 0.238) survival probability. Patients with a low mitotic count after ILP had a significantly higher OS (P < 0.001), EFS (P = 0.002) and post-relapse survival probability (P = 0.030) compared to patients with an intermediate or high mitotic count. CONCLUSIONS: The mitotic count following ILP for primary, high-grade, locally advanced, non-metastatic soft tissue sarcoma appears to significantly correlate with prognosis. If these results are validated in a prospective setting, they could provide a rationale for the design of adjuvant systemic chemotherapy trials with the goal of improving the prognosis of patients with an intermediate or high mitotic count after ILP.

Prognostic relevance of ¹8F-FDG PET uptake in patients with locally advanced, extremity soft tissue sarcomas undergoing neoadjuvant isolated limb perfusion with TNF-α and melphalan.

PURPOSE: The objective of this study was to determine whether (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) can adequately assess the risk of systemic disease progression in patients with primary, localized, high-grade soft tissue sarcomas of the extremities undergoing neoadjuvant isolated limb perfusion (ILP) with tumour necrosis factor and melphalan. METHODS: This was a retrospective analysis of the files of 35 patients who underwent a PET or PET/CT scan prior to and after ILP followed by surgical resection with curative intent between 2006 and 2012. SUVmax1 was defined as the maximum standardized uptake value (SUV) at diagnosis, SUVmax2 as the maximum SUV after ILP and ΔSUVmax as the percentage difference between SUVmax1 and SUVmax2. RESULTS: The median follow-up was 40 months for all patients. The median SUVmax1 amounted to 7.6, while the median SUVmax2 was 4.7. The median ΔSUVmax was -44%. Overall survival (OS) probability at 2 and 5 years amounted to 78 and 70%, respectively, while metastasis-free survival (MFS) probability at 2 and 5 years was 67 and 64%, respectively. Receiver-operating characteristic (ROC) curve analysis showed that both SUVmax2 and ΔSUVmax could predict systemic disease progression, while SUVmax1 could not adequately identify patients who went on to develop metastatic disease. The optimal cut-off value was 6.9 for SUVmax2 and -31 % for ΔSUVmax. Patients with an SUVmax2 <6.9 had a 2-year MFS of 80%, compared to 31 % for patients with an SUVmax2 ≥ 6.9 (p < 0.001). Patients with a ΔSUVmax < -31 %, i.e. patients with a higher metabolic response, had an MFS of 76% at 2 years, compared to 42% for patients with a ΔSUVmax ≥ -31% (p = 0.050). CONCLUSION: SUVmax after ILP for primary, locally advanced, non-metastatic high-grade soft tissue sarcomas of the extremities appears to be significantly correlated with prognosis. Whether patients with a high SUVmax after ILP will benefit from standard or experimental adjuvant systemic treatment options should be evaluated in future studies.

Bisphosphonate-osteoclasts: changes in osteoclast morphology and function induced by antiresorptive nitrogen-containing bisphosphonate treatment in osteoporosis patients.

Osteoclasts are unique cells capable of bone resorption and therefore have become a major target in osteoporosis treatment strategies. Bisphosphonates suppress bone turnover via interference with the internal enzymatic cell system of osteoclasts leading to cytoskeletal disruption. This mechanism found its clinical relevance in reducing bone resorption, stabilizing bone mass and reducing fracture risk in osteoporosis patients. However, knowledge about specific in vivo changes in osteoclast cell morphology and function is still insufficient. We examined osteoclasts in 23 paired bone biopsies from osteoporosis patients (18 males, 5 females; age: 52.6±11.5yrs) under nitrogen-containing bisphosphonate administration with a mean treatment duration of three years. Formalin-fixed, undecalcified sections were assessed by qualitative and quantitative bone histomorphometry, where the osteoclast morphology, nuclei, distribution, location as well as resorption parameters were investigated to obtain information about cell function and viability. After three years of treatment, resorption parameters decreased significantly while the number of osteoclasts remained unchanged. Out of 23 patients, nine developed previously termed "giant-osteoclasts" with increased size, numerous nuclei (>10 nuclei/Oc) and oftentimes detachment from the bone surface. These cells frequently had pycnotic nuclei and other morphological signs suggestive of osteoclast apoptosis. Characteristic large-sized osteoclasts were uniquely found in patients treated with nitrogen-containing bisphosphonates, thus being clearly distinguishable from giant-osteoclasts in other bone disorders such as Paget disease, secondary hyperparathyroidism or osteopetrosis. The resorption indices of large-sized osteoclasts, specifically the eroded perimeter and erosion depth, revealed significantly reduced values but not an entirely inhibited resorption capability. Bisphosphonate-osteoclasts' viability and affinity to bone seem significantly disturbed while the apoptotic process may be prolonged for a yet unknown period of time in favor of maintaining a low bone turnover.

Congenital osteofibrous dysplasia Campanacci: spontaneous postbioptic regression.

Osteofibrous dysplasia Campanacci is a rare benign bone tumor most frequently observed in young childhood. The exclusive localization in the tibia is very characteristic. The incidence of congenital primary bone tumors is an absolute rarity. We report a case of a newborn with a histologically proven osteofibrous dysplasia Campanacci at the tibia presenting a regular radiographic follow-up. After a small open biopsy and spontaneous minor fracture, the lesion rapidly remodeled within 1½ months and almost completely regressed with restutio ad integrum. Surgical intervention in this tumor entity at childhood age has been shown to have a high recurrence rate but due to lack of experience with newborns, guidelines do not exist. We analyze the radiologic and histologic differential diagnosis of juvenile adamantinoma and emphasize that congenital peripheral bone tumors should be treated conservatively when malignancy is excluded.

Trabecular reorganization in consecutive iliac crest biopsies when switching from bisphosphonate to strontium ranelate treatment.

BACKGROUND: Several agents are available to treat osteoporosis while addressing patient-specific medical needs. Individuals' residual risk to severe fracture may require changes in treatment strategy. Data at osseous cellular and microstructural levels due to a therapy switch between agents with different modes of action are rare. Our study on a series of five consecutively taken bone biopsies from an osteoporotic individual over a six-year period analyzes changes in cellular characteristics, bone microstructure and mineralization caused by a therapy switch from an antiresorptive (bisphosphonate) to a dual action bone agent (strontium ranelate). METHODOLOGY/PRINCIPAL FINDINGS: Biopsies were progressively taken from the iliac crest of a female patient. Four biopsies were taken during bisphosphonate therapy and one biopsy was taken after one year of strontium ranelate (SR) treatment. Furthermore, serum bone markers and dual x-ray absorptiometry measurements were acquired. Undecalcified histology was used to assess osteoid parameters and bone turnover. Structural indices and degree of mineralization were determined using microcomputed tomography, quantitative backscattered electron imaging, and combined energy dispersive x-ray/µ-x-ray-fluorescence microanalysis. CONCLUSIONS/SIGNIFICANCE: Microstructural data revealed a notable increase in bone volume fraction after one year of SR treatment compared to the bisphosphonate treatment period. Indices of connectivity density, structure model index and trabecular bone pattern factor were predominantly enhanced indicating that the architectural transformation from trabecular rods to plates was responsible for the bone volume increase and less due to changes in trabecular thickness and number. Administration of SR following bisphosphonates led to a maintained mineralization profile with an uptake of strontium on the bone surface level. Reactivated osteoclasts designed tunneling, hook-like intratrabecular resorption sites. The appearance of tunneling resorption lacunae and the formation of both mini-modeling units and osteon-like structures within increased plate-like cancellous bone mass provides additional information on the mechanisms of strontium ranelate following bisphosphonate treatment, which may deserve special attention when monitoring a treatment switch.

Quantitative MRI using T1ρ and T2 in human osteoarthritic cartilage specimens: correlation with biochemical measurements and histology.

PURPOSE: A direct correlation between T(1ρ), T(2) and quantified proteoglycan and collagen contents in human osteoarthritic cartilage has yet to be documented. We aimed to investigate the orientation effect on T(1ρ) and T(2) values in human osteoarthritic cartilage and to quantify the correlation between T(1ρ), T(2) vs. biochemical composition and histology in human osteoarthritic cartilage. MATERIALS AND METHODS: Thirty-three cartilage specimens were collected from patients who underwent total knee arthroplasty due to severe osteoarthritis and scanned with a 3T MR scanner for T(1ρ) and T(2) quantification. Nine specimens were scanned at three different orientations with respect to the B(0): 0°, 90° and 54.7°. Core punches were taken after MRI. Collagen and proteoglycan contents were quantified using biochemical assays. Histology sections were graded using Mankin scores. The correlation between imaging parameters, biochemical contents and histological scores were studied. RESULTS: Both mean T(1ρ) and T(2) at 54.7° were significantly higher than those measured at 90° and 0°, with T(1ρ) showing less increase compared to T(2). R(1ρ) (1/T(1ρ)) values had a significant but moderate correlation with proteoglycan contents (R=.45, P=.002), while R(2) (1/T(2)) was not correlated with proteoglycan. No significant correlation was found between relaxation times (T(1ρ) or T(2)) and collagen contents. The T(1ρ) values of specimen sections with high Mankin scores were significantly higher than those with low Mankin scores (P<.05). CONCLUSIONS: Quantitative MRI has a great potential to provide noninvasive imaging biomarkers for cartilage degeneration in osteoarthritis.

Teriparatide following bisphosphonates: initial and long-term effects on microarchitecture and bone remodeling at the human iliac crest.

Since the approval of teriparatide for clinical application, a number of iliac crest studies have focused on increases in bone volume or changes in structural parameters with microCT and numerical changes in histomorphometry. This investigation is based on individual histopathological observations related to early and late effects of teriparatide treatment in humans. A total of 44 (18 paired) iliac crest biopsies (ICB) from 41 patients receiving teriparatide (10 months +/- 6 months) following bisphosphonate (BP) treatment were investigated for hematopoietic changes, bone turnover, and description of microarchitectural changes using histology and selective microCT. Fully 71% of the ICB showed a normal or high bone turnover; 56% of the paired ICB presented an increase in bone turnover following teriparatide treatment. Early teriparatide stimulation (<1 month) resulted in peritrabecular fibroblast-like formations. Rare findings (<9%) included reactive hematopoietic changes, osteoidosis, endosteal fibrosis, microcallus, or woven bone. Round mast cells were frequently observed within marrow spaces. A total of 14% had an increase in cortical porosity, approximately 20% demonstrated signs of intratrabecular resorption sites. Teriparatide treatment resulted in an increase in remodeling units as early as 1 week after the first application with a continuous stimulation up to 18 months of rhPTH treatment despite previous BPs. Subgroups of patients developed increased cortical and/or intratrabecular resorption pattern, with unclear biomechanical significance. This mechanism could potentially result in new trabecular structures with an increase in trabecular number. Some individuals presented histological findings (e.g., fibrosis) that may require adjustment of treatment that could be of importance for clinical efficacy.