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Bones provide essential functions and are sites of unique biochemistry and specialized cells, but can also be sites of disease. The treatment of bone disorders and neoplasia has presented difficulties in the past, and improved delivery of drugs to bone remains an important goal for achieving effective treatments. Drug targeting strategies have improved drug localization to bone by taking advantage of the high mineral concentration unique to the bone hydroxyapatite matrix, as well as tissue-specific cell types. The bisphosphonate molecule class binds specifically to hydroxyapatite and inhibits osteoclast resorption of bone, providing direct treatment for degenerative bone disorders, and as emerging evidence suggests, cancer. These bone-binding molecules also provide the opportunity to deliver other drugs specifically to bone by bisphosphonate conjugation. Bisphosphonate bone-targeted therapies have been successful in treatment of osteoporosis, primary and metastatic neoplasms of the bone, and other bone disorders, as well as refining bone imaging. In this review, we focus upon the use of bisphosphonate conjugates with antineoplastic agents, and overview bisphosphonate based imaging agents, nanoparticles, and other drugs. We also discuss linker design potential and the current state of bisphosphonate conjugate research progress. Ongoing investigations continue to expand the possibilities for bone-targeted therapeutics and for extending their reach into clinical practice., Highlights • The ideal bone-targeting drug treats disease and preserves normal bone function. • Bisphosphonate affinity for bone mineral is an ideal foundation for specific targeting of drug to the bone. • Three critical elements: (i) drug payload, (ii) bisphosphonate, and (iii) type of conjugation determine PK and PD activity. • Two promising bisphosphonate-conjugates are currently in clinical oncology trials. • Understanding the payload, bisphophonate and conjugate PK/PD metrics is needed to realize the full potential of this approach.

18F-sodium fluoride (18F-NaF) PET/CT provides high sensitivity and specificity for the assessment of bone and joint diseases. It is able to accurately differentiate malignant from benign bone lesions, especially when using dynamic quantitative approaches. Its high-quality, clinical accuracy, and high feasibility for patient management and greater availability of PET/CT scanners as well as decreasing trend of the cost of radiotracer all indicate the need to consider the use of 18F-NaF PET/CT as standard bone imaging, particularly in malignant diseases of the skeleton.

Summary An accumulation of fatigue-induced microdamage can often result in an overall thinning and weakening of the bone's structure through a reduction in its mass, which increases its fragility and makes an individual more susceptible to fractures. Consequently, it is vitally important to detect and quantify microdamage early in order to diagnose skeletal diseases and combat their progression. Herein, we present the synthesis and study of europium [Eu(III)]-emitting surface-modified gold nanoparticles as contrast agents for imaging microdamaged bone structure at low concentrations. These nanostructures can be utilized to generate three-dimensional maps (z stacking) of microcracks formed within bone. Using two-photon excitation fluorescence microscopy, we were able to visualize and understand the manner in which these nanoagents bind to damaged bone, as well as demonstrate their selectivity toward exposed Ca(II) within microcracks. Such systems are therefore ideal for biological application as targeted contrast agents for both optical imaging and MRI.

Phosphonates-based agents are well-known bone-seeking radiopharmaceuticals with application in detection and therapy. With higher sensitivity and resolution offered by Positron Emission Tomography (PET), tracers based on this technique are gaining huge attention. 68Ga-based generator and radiotracers render independence from the on-site cyclotron. We report the development of 68Ga-labeled DOTA-based bismacrocyclic phosphonate derivative, for bone PET imaging. The synthesis and characterization of 68Ga- DO3P-AME-DO3P was carried out in > 95% purity. The radiotracer displayed high stability and low binding affinity (

This work provides an estimation of the exposure of the Portuguese population to ionizing radiation due to radiodiagnostic (x-ray and nuclear medicine (NM)) procedures, between 2013 and 2017, using the methodology proposed by the European Commission. Obtained results show that the estimated annual mean effective dose to the Portuguese population due to x-ray procedures increased by about 16%, from 0.75 ± 0.48 mSv per caput in 2013 to 0.89 ± 0.56 mSv per caput in 2017. The x-ray exam type that contributes the most to the collective dose in Portugal is Computed Tomography (CT). In the case of nuclear medicine, an increase in the annual effective dose from 0.088 ± 0.001 mSv per caput in 2013 to 0.090 ± 0.002 mSv per caput in 2017 was observed, with the procedures that contribute the most to the collective dose being bone imaging and cardiac procedures. This study intends to raise awareness to the need of optimization of radiation dose in medical procedures.

Background Pembrolizumab (pembro) is the standard of care for patients (pts) with locally advanced or metastatic urothelial carcinoma who are cisplatin-ineligible with tumors expressing programmed death ligand 1 (PD-L1) and for pts unable to receive platinum-based chemotherapy regardless of PD-L1 status, based on KEYNOTE-052 (NCT02335424). Lenvatinib is a potent multiple-receptor tyrosine kinase inhibitor that selectively inhibits VEGF, VEGFR1-3, FGFR1-4, PDGFRα, c-kit, and RET and was found to have activity in multiple solid tumors. In KEYNOTE-146 (NCT02501096), the combination of lenvatinib and pembro showed promising efficacy and manageable safety in previously treated pts with advanced urothelial carcinoma, regardless of PD-L1 status. Trial design LEAP-011 (NCT03898180) is a randomized, double-blind, multicenter, global, phase 3 trial to test the hypothesis that the addition of lenvatinib to first-line pembro in advanced UC may improve outcomes compared to pembro/placebo. Eligible pts are adults with histologically confirmed locally advanced unresectable or metastatic urothelial carcinoma, that are either cisplatin-ineligible with tumors expressing PD-L1 (combined positive score ≥10), or that are ineligible to receive any platinum-based chemotherapy. Pts have not been previously treated with systemic chemotherapy for advanced urothelial carcinoma, have an ECOG PS score of 0-2, and have tumor tissue for PD-L1 analysis. About 694 pts will be enrolled and randomly assigned 1:1 to receive up to 35 cycles (2 y) of pembro 200 mg IV every 3 weeks with either lenvatinib 20 mg or placebo orally QD. Radiologic assessment will include CT/MRI of the chest, abdomen, or pelvis and bone imaging. Responses will be assessed per RECIST v1.1 by blinded independent central review. Dual primary end points are PFS and OS. Secondary end points are objective response rate, response duration, safety/tolerability, and disease control rate. Tissue-and blood-based biomarkers will be explored. Adverse events (AEs; graded per NCI CTCAE v4.0) will be monitored from randomization through 30 days after last dose of study drug (90 days for serious AEs). Clinical trial identification NCT03898180; April 1, 2019. Editorial acknowledgement Matthew Grzywacz, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure Y. Loriot: Honoraria (self), Honoraria (institution), Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Honoraria (institution): BMS; Honoraria (self), Honoraria (institution): Clovis; Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: Seattle Genetics; Honoraria (self), Honoraria (institution): Pfizer; Honoraria (self), Honoraria (institution), Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Honoraria (institution): Astellas; Honoraria (institution): Exelixis; Honoraria (institution): Nektar; Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Sanofi. A. Balar: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genentech; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Pfizer/EMD Serono. R. de Wit: Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Honoraria (institution), Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Research grant / Funding (institution): Bayer; Honoraria (self): Janssen; Advisory / Consultancy: Clovis. J.A. Garcia: Advisory / Consultancy: Merck; Honoraria (self), Research grant / Funding (institution): Eisai. P. Grivas: Advisory / Consultancy: Merck & Co., Genentech, Dendreon, Bayer, Pfizer, Bristol-Myers Squibb, Exelixis, AstraZeneca, Biocept, Clovis Oncology, EMD Serono, Seattle Genetics, Foundation Medicine, Driver Inc., QED Therapeutics, Heron Therapeutics, Janssen; Speaker Bureau / Expert testimony, Educational unbranded activity: Genentech, Bristol-Myers Squibb; Travel / Accommodation / Expenses: AstraZeneca, Clovis Oncology; Research grant / Funding (institution): Merck & Co., Genentech, Bayer, Mirati, Oncogenex, AstraZeneca, Pfizer, Clovis Oncology, Bavarian Nordic, Immunomedics. N. Matsubara: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): BAYER; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): SANOFI; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): MSD; Advisory / Consultancy, Research grant / Funding (self): Roche; Advisory / Consultancy: Lilly; Speaker Bureau / Expert testimony: Chugai; Research grant / Funding (self): Eisai. T.L. Frenkl: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck; Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment, Spouse, employment and travel/accommodations/expenses: Amicus Therapeutics; Leadership role, Spouse, on board of directors for VenatoRx: VenatoRx; Shareholder / Stockholder / Stock options: GSK; Shareholder / Stockholder / Stock options: AstraZeneca. E. Sbar: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: MSD; Shareholder / Stockholder / Stock options: BMS; Shareholder / Stockholder / Stock options: Pfizer. X.C. Jia: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. A.O. Siefker-Radtke: Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharp & Dohme; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Travel / Accommodation / Expenses: Nektar Therapeutics; Advisory / Consultancy, Travel / Accommodation / Expenses: Seattle Genetics; Advisory / Consultancy: Bavarian Nordic. All other authors have declared no conflicts of interest.

Part II of this 3-part series demonstrated 1-yr precision, standard error of the estimate, and 1-yr least significant change for volumetric bone outcomes determined using peripheral (p) quantitative computed tomography (QCT) and peripheral magnetic resonance imaging (pMRI) modalities in vivo. However, no clinically relevant outcomes have been linked to these measures of change. This study examined 97 women with mean age of 75 ± 9 yr and body mass index of 26.84 ± 4.77 kg/m 2 , demonstrating a lack of association between fragility fractures and standard deviation, least significant change and standard error of the estimate-based unit differences in volumetric bone outcomes derived from both pMRI and pQCT. Only cortical volumetric bone mineral density and cortical thickness derived from high-resolution pQCT images were associated with an increased odds for fractures. The same measures obtained by pQCT erred toward significance. Despite the smaller 1-yr and short-term precision error for measures at the tibia vs the radius, the associations with fractures observed at the radius were larger than at the tibia for high-resolution pQCT. Unit differences in cortical thickness and cortical volumetric bone mineral density able to yield a 50% increase in odds for fractures were quantified here and suggested as a reference for future power computations.

To esthetically and functionally restore a 40-mm canine mandibular discontinuity defect using a custom-made titanium bone-grafting plate in combination with autologous iliac bone grafts. Individualized titanium bone-grafting plates were manufactured using a series of techniques, including reverse engineering, computer aided design, rapid prototyping and titanium casting. A 40-mm discontinuous defect in the right mandibular body was created in 9 hybrid dogs. The defect was restored immediately using the customized plate in combination with autologous cancellous iliac blocks. Sequential radionuclide bone imaging was performed to evaluate the bone metabolism and reconstitution of the grafts. The specimens were evaluated by biomechanical testing, 3-dimensional microcomputed tomographic scanning, and histological examination. The results revealed that the symmetry of the mandibles was reconstructed using the customized grafting plate, and the bony continuity of the mandibles was restored. By 12 weeks after the operation, the cancellous iliac grafts became a hard bone block, which was of comparable strength to native mandibles. A fibrous tissue intermediate was found between the remodelled bone graft and the titanium plate. The results indicate that the prototyped grafting plate can be used to restore mandibular discontinuous defects, and satisfactory aesthetical and functional reconstruction can be achieved.

Background We report secondary and exploratory analysis with 18F-NaF PET/CT and CTCs to determine how tumour burden and RNA expression of androgen receptor (AR) splice variants and neuroendocrine (NE) features predict duration of treatment (DoTx) with ENZA. Methods Men with progressive mCRPC with ≥ 2 lesions on bone scintigraphy were enrolled and treated with ENZA 160 mg daily at 3 US sites. 18F-NaF PET/CT scans were obtained at baseline (BL) (PET1), week 13 (PET2), and at the time of PSA progression (per PCWG2 criteria), standard radiographic or clinical progression, or at 2 years without progression (PET3) using QTBI. CTCs were obtained at BL and at PET3. PSA decline and DoTx were compared with BL QTBI, CTC metrics, and change in QTBI. Results 23 men (median age, 72 years [range, 51-93]; median PSA, 20.5 ng/mL [range, 3.9-133.6]) were enrolled; 22 of which completed planned imaging. The mean number of bone lesions on PET1 was 58 (range 9-168), with a median total standardized uptake value (SUVtotal) of 3886.5 (range 506.7-22852.8). DoTx ranged from 1.4 to 31.8+ mo. In general, SUV metrics decreased while on ENZA (PET2) and increased by PET3. Change in lesion heterogeneity (PET1 to PET3) was the most significant predictor of time to PSA progression (hazard ratio, 3.88; 95% confidence interval, 1.24-12.1). ARV7/9 was found in CTCs in 3/20 men and NE features were found in 4/20 men at BL and in 4/19 and in 11/19 men, respectively, at PET3. Conclusions Although PSA response with ENZA is high, DoTx is variable. SUVtotal at BL did not correlate with DoTx; however, decrease in SUVtotal/mean was associated with increased DoTx, with less heterogeneity correlating with a longer time to PSA progression. ARV7/9 or NE expression in CTCs did not predict lack of benefit from ENZA; however, at the time of progression, the observed increase in ARV7/9 and NE expression are consistent with tumor evolution to more aggressive phenotypes. While BL heterogeneity may be prognostic, it may not predict response or DoTx. Assessing response heterogeneity may predict response duration, thus, should be explored as a possible surrogate of benefit in future studies. Clinical trial identification NCT02384382. Editorial acknowledgement Medical writing and editorial assistance funded by Pfizer Inc. and Astellas Pharma, Inc. was provided by Stephanie Vadasz, PhD, and Michele Salernitano from Ashfield Healthcare Communications. Legal entity responsible for the study Pfizer Inc. and Astellas Pharma, Inc. Funding Pfizer Inc. and Astellas Pharma, Inc. Disclosure G. Liu: Leadership role, Shareholder / Stockholder / Stock options, Employee: AIQ Solutions; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Novartis; Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): TRACON Pharma; Research grant / Funding (self), Research grant / Funding (institution): Madison Vaccines Inc.; Research grant / Funding (self), Research grant / Funding (institution): Pfizer Inc. C.E. Kyriakopoulos: Advisory / Consultancy, Travel / Accommodation / Expenses: Exelixis; Speaker Bureau / Expert testimony: The France Foundation; Research grant / Funding (self), Research grant / Funding (institution): Sanofi. J.M. Lang: Shareholder / Stockholder / Stock options, Licensing / Royalties, I am listed on the patent on a technology for rare cell capture and analysis. This technology has been licensed by Salus Discovery, LLC though no commercial products are available: Salus Discovery; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Pfizer Inc.; Research grant / Funding (institution): Novartis. E.I. Heath: Advisory / Consultancy, Research grant / Funding (institution): Agensys; Honoraria (self), Speaker Bureau / Expert testimony: Sanofi; Honoraria (self): Bayer; Honoraria (self), Research grant / Funding (institution): Dendreon; Honoraria (self), Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Tokai Pharmaceuticals; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Inovio Pharmaceuticals; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Zenith Epigenetics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Esanik; Research grant / Funding (institution): Oncolys BioPharma; Research grant / Funding (institution): CureMeta; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): eFFECTOR Therapeutics; Research grant / Funding (institution): Fortis. S. Perlman: Research grant / Funding (institution): GE Healthcare Progenics; Advisory / Consultancy: Pfizer Inc. T. Mayer: Advisory / Consultancy: Beacon Biosciences/ICON Medical; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Research grant / Funding (institution): Sotio; Research grant / Funding (institution): Merck; Research grant / Funding (self): Pfizer Inc. K. Modelska: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Employee: Pfizer Inc. A. Porcari: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Employee: Pfizer Inc. W. Duggan: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Employee: Pfizer Inc. R. Jeraj: Licensing / Royalties, Patents: Wisconsin Alumni Research Foundation; Shareholder / Stockholder / Stock options: AIQ Solutions; Research grant / Funding (institution): GE Healthcare. All other authors have declared no conflicts of interest.

Cancers prone to spread to bone include prostate, lung, kidney, breast and thyroid cancers. While bone scanner has been widely used in the past decades, PET-based imaging modalities are increasingly used. Current modalities of PET imaging of bone metastases include tumor and inflammatory targeting with FDG-PET, bone imaging with NaF-PET, and direct cancer-specific markers such as FDOPA-PET or PET using choline. The cancer-specific metastatic patterns and the relative prognosis conferred by osseous metastases (versus visceral metastases) may determine the need for bone scan, FDG-PET for the detection of bone metastases. Because some cancers have a mixed skeletal and visceral, cocktails PET radiopharmaceuticals may also be discussed in the future. The cancer-specific context and performances of bone scan and PET imaging are discussed.

The current protocols include the bone scintigraphy and choline PET/CT to localize recurrence in patients having elevated serum PSA after treatment for prostate cancer. Both methods show good agreement in the diagnosis of bone metastases; however, conflicting results can be found. We present three cases in which a PET/CT was performed with 18 F-fluoride due to disagreement between the bone scintigraphy and 11 C-choline PET/CT. The 18 F-fluoride PET/CT was capable of confirming the existence of bone metastasis in all of them, so it may be an alternative to the MRI as a tracer of second bone imaging modality, although its use is limited by cost and availability.

We used high-resolution quantitative computed tomography to study the microarchitecture of bone in patients with chronic kidney disease on dialysis. We compared bone characteristics in 56 maintenance hemodialysis (21 women, 14 post-menopausal) and 23 peritoneal dialysis patients (9 women, 6 post-menopausal) to 79 healthy men and women from two cohorts matched for age, body mass index, gender, and menopausal status. All underwent dual-energy X-ray absorptiometry of the spine and hip to measure areal bone mineral density, and high-resolution peripheral quantitative computed tomography of the radius and tibia to measure volumetric bone mineral density and microarchitecture. When compared to their matched healthy controls, patients receiving hemodialysis and peritoneal dialysis had a significantly lower areal bone mineral density in the hip. Hemodialysis patients had significantly lower total, cortical, and trabecular volumetric bone mineral density at both sites. Hemodialysis patients had significantly lower trabecular volumetric bone mineral density and microarchitecture at the tibia than the peritoneal dialysis patients. Overall, peritoneal dialysis patients were less affected, their cortical thickness at the distal tibia being the only significant difference versus controls. Thus, we found more severe trabecular damage at the weight-bearing tibia in hemodialysis compared to peritoneal dialysis patients, but this latter finding needs confirmation in larger cohorts.

Conventional planar and SPECT bone scintigraphy has long been used and familiarity with this tracer and imaging technique is excellent. (18)F NaF PET/CT represents an alternative tracer and imaging modality for the assessment of the skeleton, with the potential to become the gold standard in functional bone imaging. This article compares the pharmacokinetics, protocols, clinical performance, and cost-effectiveness of the 2 modalities. Technological advances and future directions of both modalities are also discussed.

Purpose To esthetically and functionally restore a 40-mm canine mandibular discontinuity defect using a custom-made titanium bone-grafting tray packed with autologous iliac bone. Materials and Methods Individualized titanium bone-grafting trays were made using a reverse engineering, computer-aided design, and rapid prototyping technique. A 40-mm discontinuity defect in the right mandibular body was created in 10 hybrid dogs. The defect was restored immediately using the tray that was densely packed with autologous cancellous iliac particles and covered with trimmed iliac chips. Sequential radionuclide bone imaging was performed postoperatively at 2, 4, 8, 12, and 24 weeks. The ratio of activity between the grafted mandible and the contralateral native mandible on each transaxial slice was calculated. The mean activity ratio was analyzed at each time point to evaluate the bone metabolism and reconstitution of the grafts. The subjects were sacrificed at 4, 12, and 24 weeks after grafting. The specimens were evaluated by postmortem gross dissection, biomechanical testing, 3-dimensional microcomputed tomographic scanning, and histologic examination. Results All the subjects tolerated the grafting operation well. Over an observation period of 24 weeks, tray extrusion occurred in 3 of the 10 subjects. Bony continuities were reconstructed in 9 of the 10 subjects. Radionuclide bone imaging revealed that the tracer uptake increased in the grafted mandible, and the radionuclide ratio between the graft and the native mandible decreased with time. Gross evaluation, microcomputed tomographic examination, biomechanical testing, and histologic examination demonstrated corticalization of the grafts. Conclusions The use of a customized technique using reverse engineering, computer-aided design, and rapid prototyping tray containing autologous cancellous bone is a potentially powerful grafting technique for the reconstruction of mandibular discontinuity defects.

A novel zoledronic acid (ZL) derivative, 1-hydroxy-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)ethane-1,1-diyldiphosphonic acid (EMIDP), was prepared and labeled with 99 m Tc successfully in a high labeling yield and good stability in vitro. The preclinical pharmacological properties of 99 m Tc-EMIDP were investigated and compared with 99 m Tc-MDP and 99 m Tc-ZL. The studies of biodistribution in mice and SPECT bone imaging of the rabbit suggest that 99 m Tc-EMIDP has highly selective uptake in the skeletal system and rapid clearance in the soft tissues. The present findings indicate that 99 m Tc-EMIDP holds great potential for bone scintigraphy.

Nuclear medicine has entered a new era of multimodality imaging. Dedicated multislice single-photon emission computed tomography/computed tomography (SPECT/CT) cameras are relatively new additions to the diagnostic armamentarium in nuclear medicine. The integration of SPECT and CT provides precise anatomical localization and may enable characterization of abnormalities identified on planar or SPECT imaging by providing structural information by CT. The evidence in support of SPECT/CT is rapidly amounting but still relatively limited. To date, studies have suggested improved diagnostic confidence and specificity in the diagnosis of bone pathology. The combination of functional information and anatomical localization has the potential to influence medical practice with newer imaging algorithms. This review presents the current evidence and potential indications of SPECT/CT bone imaging in the assessment of benign and malignant conditions.

Bone scintigraphy is one of the most common investigations performed in nuclear medicine and is used routinely in the evaluation of patients with cancer for suspected bone metastases and in various benign musculoskeletal conditions. Innovations in equipment design and other advances, such as single-photon emission computed tomography (SPECT), positron emission tomography, positron emission tomography/computed tomography (CT), and SPECT/CT have been incorporated into the investigation of various musculoskeletal diseases. Bone scans frequently show high sensitivity but specificity, which is variable or limited. Some of the limited specificity can be partially addressed by a thorough knowledge and experience of normal variants and common patterns to avoid misinterpretation. In this review, we discuss the common patterns, variants, artifacts, and pitfalls in conventional radionuclide planar, SPECT, and hybrid bone (SPECT/CT) imaging.

Wide-field polarized light and epifluorescence microscopy have been used to enhance analysis of archaeological bone tissue, providing information on bone formation, modeling, pathology, preservation, age estimation, and biomechanics. Though valuable, these techniques are limited by their inability to remove out-of-focus light and view multiple levels of a sample, restricting our understanding of the three-dimensional (3-D) microarchitecture of compact bone. Modern technological advances, such as microscopic computerized tomography, allow increasing resolution in 3-D bone imaging, but do not allow fluorescence labeling or polarized-light analysis. Confocal laser scanning microscopy (CLSM) is a valuable tool for 3-D histology. However, its application to the study of compact bone is lacking, especially in archaeological and forensic sciences. The current study investigated CLSM as a tool for fluorescence and polarized-light microscopy of archaeological compact bone in order to demonstrate its advantages. Standard techniques and CLSM are compared in their suitability for imaging well preserved archaeological bones from the Dakhleh Oasis, Egypt. CLSM's high resolution, multi-channel, two- and three-dimensional capabilities augment the flexibility and creativity of compact bone imaging and have the potential to increase the accuracy of quantitative medical and anthropological histomorphometric techniques. CLSM is specifically suggested as a useful tool for the investigation of ancient bone fluorescence caused by the presence of tetracycline and/or other fluorochromes.

TADP, 2-(1H-1, 2, 4-triazol-1-yl)-1-hydroxyethane-1, 1-diphosphonic acid, was synthesized by three step reactions from the raw material 1H-1, 2, 4-triazole. 99Tcm-TADP was prepared with 5 mg TADP at pH 7.0 by joining 99TcmO4−with SnCl2–2H2O in aqueous solution for 10 min at room temperature. Both labeling yield and radiochemical purity of 99Tcm-TADP were more than 95%. The biodistribution in rats and bone scan in rabbits were also studied. The uptake of organ was expressed as %ID/g. The results showed that the bone uptake is up to 17.17%ID/g which is the maximum of bone uptake at 30 min after injection of 99Tcm-TADP in rats, bone-to-muscle and bone-to-blood uptake ratios were 61.32 and 13.21, respectively. The clear bone image of rabbit was obtained at 120 min after injection of 99Tcm-TADP and clearance in soft tissue was visible. The preparation of 99Tcm-TADP was convenient and 99Tcm-TADP exhibited high uptake in bone, and it would be a potential new bone imaging agent.

Finite element analysis ( FEA ) is the method of choice to nondestructively quantify stresses and strains in bones. Moderate to good estimates of bone strength can be obtained from continuum-level FEA. Improved predictive capacity is expected from microstructural FE models that represent the trabecular architecture in detail. With the advent of recently developed high-resolution in vivo bone imaging systems and the steady increase in computational power, such microstructural FE analyses are now becoming available to estimate bone strength in humans in a clinical setting. The procedure can help improve predictions of fracture risk, clarify the pathophysiology of skeletal diseases, and monitor the response to therapy.

In this issue of Chem , Gunnlaugsson and colleagues show that using a luminescent Eu III cyclen complex with a sensitizer capable of two-photon excitation leads to unprecedented in-depth high-resolution imaging of microcracks in bone at a 750 nm excitation wavelength.

99mTc-HEDP is widely used as a bone imaging agent and its Re analog [186Re]Re-HEDP is now well established as a therapeutic radiopharmaceutical for palliation of pain due to bone metastases. In the present paper, we report the work carried out for the preparation of stable 186Re-HEDP which retains RC purity up to 5 days when stored at 4 degrees C. 186Re was prepared by irradiation of natural Re metal at a flux of 3 x 10(13) neutrons/cm2/s for seven days and processed after a cooling period of four days. The specific activity of 186Re formed was approximately 35 mCi/mg. A complex with RC purity > 98% could be prepared by varying the reaction conditions. By carefully optimizing the reaction and storage conditions, a complex which was stable for over 4 days could be synthesized. Bio-distribution studies carried out in rats revealed approximately 30% bone uptake of 186Re-HEDP at 3 h postinjection which remained almost constant for 48 h, at which time there was negligible activity in other organs.

Reflex sympathetic dystrophy, (RSD) is a complex physiologic response of the body to an external stimulus resulting in sympathetically mediated, usually nonanatomic pain, which is out of proportion to the inciting event or expected healing response. This complex entity has been the focus of much investigation, leading however to somewhat confusing and conflicting results and theories about the etiology and pathophysiology. There is even significant conflict about what characteristics define the clinical entity called RSD, and if these characteristics vary with the specific site of involvement. We have examined the current literature regarding these fundamental conflicts, and in addition we have evaluated the current controversies surrounding the role of Three Phase Radionuclide Bone Imaging (TPBI) for diagnosis, prognosis, and patient management. These controversies include the role of scintigraphy, the various criteria for scintigraphic diagnosis, and the reported variations in sensitivity and specificity of TPBI in RSD. We have examined several factors that may have affected these results, and potentially underestimated the value of scintigraphy in the diagnosis of RSD. In addition to the heterogeneous patient populations used to establish the diagnosis by different subspecialty physicians, these factors include duration of patient's symptoms, age of the patient population evaluated, location of the disease, and the varying scintigraphic scan interpretation criteria used.

Along with resurgence of physical activity during these fitness conscious times, there is increasing participation by people of all ages in sporting activities. Enrollment in organized and recreational sports among young adults and children has increased with as many as 30% of adolescents participating in competitive high school athletics. Despite improvements in equipment, the number of sports-related injuries presenting for medical attention has increased. Injuries to the upper extremities account for more than 25% of all sports-related injuries, but receive disproportionately less attention compared to lower extremity injuries. If neglected, upper extremity injuries can end the career of a professional athlete and cause sufficient damage to hinder daily activities in a recreational participant. Overuse syndromes, brought on by repetitive microtrauma are sports-specific, and often challenging to diagnose. Accurate diagnosis requires a thorough understanding about mechanism of injury, site of pain, and knowledge of the sport. After a thorough physical exam, a variety of radiographic testing is often necessary to promptly diagnose and manage the injury so athletes can return to competition as soon as possible.

Carpal trauma often results in scaphoid injury. A small group of patients have clinical evidence of scaphoid fracture but radiographs fail to demonstrate bony damage. Persistent pain warrants isotope bone scanning. This report reviews the results of 36 consecutive bone scans performed for the suspected scaphoid injury and reviews radiographs taken on presentation. In all, 18 diagnosed fractures: there were three of the scaphoid, six of the distal radius and nine of other carpal bones. It was possible, with hindsight, to see eight fractures on the original radiographs. In patients with continued pain over the radial side of the carpus, attention should be given to the other carpal bones and the distal radius and not just the scaphoid.

Seventy-two joint arthroplasties undergoing total hip or total knee surgery were studied prospectively with plain radiographs, three-phase bone imaging (3PBI), erythrocyte sedimentation rate (ESR), aspiration of the joint for culture, and multiple intraoperative cultures at the time of revision. Intraoperative cultures and the operative appearance were used to form a diagnosis of definite infection (unequivocal microbiology and gross sepsis), possible infection (positive microbiology or gross sepsis), or no infection (neither positive microbiology nor gross sepsis). For the preoperative diagnosis of infection, as opposed to aseptic loosening, 3PBI alone had a sensitivity of 33% and a specificity of 86%. In conjunction with plain radiographs, minimal improvement in accuracy was seen. A preoperative ESR greater than 30 had low sensitivity (60%) and a specificity of (65%). However, the ESR was statistically significantly higher in the joints with definite infection as compared to those joints without infection. The preoperative joint aspiration had a sensitivity of 67% and a specificity of 96% and, therefore, appears to be the most useful single test in the workup of a painful total joint arthroplasty.

This study compares the six commercially available kits for preparing methylene diphosphonate. The kits were randomly assigned to 134 bone examinations such that neither the physicians nor the technologists knew which brand of tracer was used. Thigh activity quantitatively varied significantly among the kits (P = 0.019). Detectable gastric activity also varied by brand. Other qualitative and quantitative measures of bone and soft tissue uptake showed no significant differences among the kits but consistently favored the Squibb product.

From October 2000 to October 2005, 25 men with a rising PSA leveland biopsy-proven, intraprostatic cancer at least 2 years after initial RT (externalbeam in 13 men and brachytherapy in 12 men) who had favorable clinical fea-tures (Gleason score 7, PSA

Ambiguities in diagnoses can often be resolved when images from different imaging modalities are compared, and when images are processed with algorithms that improve resolution and contrast. Bayesean deblurring algorithms were developed and applied to Planar and SPECT images of the maxillofacial and temporomandibular joint regions. The combined use of Planar and SPECT imaging with Bayesean deblurring were complementary and provided more diagnostic information than either modality individually. A facial imaging protocol using Planar and SPECT imaging and Bayesean deblurring is described. SPECT maxillofacial anatomy is presented, as well as the application of the imaging protocol of craniomandibular dysfunction. Although not recommended for all patients with craniomandibular disorders, combined use of Planar and SPECT images and Bayesean deblurring techniques appears to be useful in diagnostically difficult or refractory cases.

Bone imaging provides two significant advantages over previously available methods for assessing bone processes. First, as scanning is non-invasive, it offers the operator the ability to sequentially follow any area of bone without altering it as would a biopsy. The second advantage is the ability of bone imaging to provide current information about the bone being scanned rather than having to deal with the delay that is inherent in conventional radiography. Recent developments in radiopharmaceuticals and instrumentation have made bone imaging a potentially practical clinical tool for the detection and assessment of benign as well as malignant processes affecting bone. This paper presents the results of the use of technetium 99m diphosphonate bone imaging in experimental canine mandibular autografts and surgical soft tissue injury. The implication of these results for the clinical situation will be discussed.

Nuclear medicine has developed some highly specialized techniques for investigating the child suspected of having a neoplastic process. These developments include improved gamma camera systems with high resolution and establishment of technetium-99m radiopharmaceuticals, especially technetium phosphate compounds for bone imaging. This has resulted in rapid growth and use of nuclear techniques for the investigation of pediatric neoplasia.

Tetramethylenephosphonate derivatives of norborane (TPNB) and dicyclopentadiene (TPDCPD) were shown to readily form stable chelates with 99mTc that had high and selective bone uptake. The skeletal uptake and blood clearance properties of 99mTc-TPNB were similar to 99mTc-MDP in both rats and rabbits. This suggests additional studies to further evaluate 99mTc-TPNB or perhaps other large-organic based multidentate phosphonate ligands as potential bone imaging agents is warranted.

A number of bone lesions are detectable by means of skeletal imaging with injected, short-lived, bone-seeking radiopharmaceuticals. These include osteonecrosis,l> 2 osteoarthritis,3 infectious spondylitis,4 primary5 and metastaticj tumors, fractures,? and osteomyelitis. s High concentrations of radioactivity in surrounding areas of new bone formation *, 5* o facilitate the localization of a lesion with externally placed radiation-measuring devices. Since the method is sensitive to small changes in the rates of local bone formation in the early stages of disease, it can often detect skeletal lesions before they are recognizable on radiographs. This clinical tool, therefore, provides diagnostic information of a metabolic or functional nature. In the present study we have attempted to apply this nondestructive method to a study of metabolic events in alveolar bone supporting orthodontically treated teeth in dogs. The objectives of the study were to determine whether bone-seeking radionuclide methods could (1) provide longitudinal metabolic information through repeated measurements of the same animal, (2) distinguish the effects of orthodontic and orthopedic forces of different magnitudes, and (3) measure separately the metabolic events occurring in areas of pressure and tension. In addition, two different radiation-detection systems were used for the collection of data, and their usefulness as research tools in dentistry was evaluated and compared.

Locally aggressive benign lesions of the jaws, such as odontogenic keratocysts and ameloblastomas, require complete excision in view of the high incidence of recurrence after incomplete surgical removal. Because of the limitations of conventional radiology as the sole technique for determining the extent of these lesions, the use of 99m-technetium-labeled bone-imaging agents is suggested. This method of defining the location of surgical margins is based on the agent's sensitivity as an indicator of subtle changes in bone metabolism. A case of an unusually large recurrent odontogenic keratocyst is presented in which the planning of the surgical procedure was predicated on the results of a bone scan of the jaws in addition to conventional radiology. This diagnostic procedure, especially when used in conjunction with conventional radiology, appears to be of considerable value in defining the extent of a variety of oral-maxillofacial bony lesions.

Extraosseous tumor uptake of bone imaging agents is a fairly frequent phenomenon but the exact mechanism of the phenomenon remains uncertain. We are reporting a case of uptake of [ 99m Tc]MDP in malignant melanoma metastatic to the liver and present a gamut for the localization of bone imaging radiopharmaceuticals within the liver. The proposed mechanisms of uptake in hepatic tumors are reviewed.

A high resolution cadmium telluride probe was used in conjunction with standard bone imaging methods in two cases of facial asymmetry. The probe improved localization of the abnormalities and led to rational treatment.

Radionuclide imaging provides a functional as well as anatomic evaluation of bone and is particularly valuable in diagnosis, staging, and management of oncologic disorders, in differentiation of inflammatory conditions and trauma, and in hypovascular disorders of bone. The practitioner should be aware of those areas in which bone imaging is clinically effective for patient care. Radionuclide bone imaging is efficacious, delivers minimal radiation, and offers a functional method of evaluation for children with skeletal disorders.

Fifty-nine patients with Legg-Perthes disease and 12 others were studied using 99m Tc-polyphosphate and the pinhole collimator imaging technique. Radiographs of both hips were correlated with images in each patient. In the Legg-Perthes patients, a radionuclide uptake deficiency of variable size was observed in the proximal femoral epiphysis (EOC), which we believe is related to varying degrees of impaired blood supply. During later disease stages, adjacent zones of increased radionuclide activity or revascularization were observed that would replace the uptake defect eventually. Unless radiographic evidence of new bone formation was observed in the EOC, it was impossible to predict either the presence or extent of revascularization until bone imaging was done. Those patients with revascularization activity in the EOC exhibited a relatively short time interval (average, 3.2 months) before evidence of new bone formation radiographically. Others with increased radionuclide concentration limited to the growth plate and/or metaphysis averaged a much longer 7.8 months. In two patients there was a reversal of the initially increased activity in the growth plate, suggesting another vascular insult. There were no false-negative bone-image findings in the 12 cases that clinically and/or radiologically simulated Legg-Perthes disease. Our image studies correlate well with published histopathologic investigations, indicating to us that assessment of extent of pathologic involvement and of the disease caurse is facilitated by this technique. Subsequently, this could influence treatment selection and provide a more objective baseline from which to judge treatment results. Continued experience suggests pinhole bone imaging has useful clinical application in Legg-Perthes disease and other childhood hip disorders.

Because of its sensitivity to minor variations in radiographic density and its ability to eliminate overlapping because of the cross-sectional display, computed tomography (CT) of the skeletal system may yield valuable information that may not be apparent on plain film or radionuclide examination of bone lesions. The authors present five case illustrations in which CT examination of bone was particularly helpful in the evaluation of the patient.

A case of polyostotic fibrous dysplasia is presented in which the extent of bony lesions was defined on the results of the CT scan and bone scan with 99m Tc polyphosphate in addition to conventional radiography. These diagnostic procedures appear to be of considerable value in defining the extent of a variety of oral-maxillofacial bony lesions. This report describes the comparative findings from 99m Tc polyphosphate bone imaging and computed tomography (CT) in one patient with polyostotic fibrous dysplasia.

Low levels of electrical current have been shown to affect the process of osseous repair. This study experimentally evaluated the effect of electrical stimulation on the healing of freeze-dried mandibular allogeneic bone grafts in dogs. Healing of the grafts was monitored by sequential submento-occlusal radiographs and radionuclide bone imaging at two, four, six, and eight weeks after grafting. Results indicated no significant difference in the osseous repair of stimulated and nonstimulated freeze-dried allogeneic bone grafts.

A comparison was made between the external detection of an injected, bone-seeking radiopharmaceutical, technetium-99m-polyphosphate (Tc-PP), and intraoral radiography in the diagnosis of acute pulp infections of dog molars resulting in apical radiolucencies. Skeletal radioactivity was measured qualitatively by bone imaging and quantitatively with a small semiconductor probe inserted in the oral cavity. Both radionuclide methods detected abnormally high Tc-PP uptake at the root apices within 1 week of infection as opposed to 4 weeks required for the appearance of periapical radiolucencies. However, Tc-PP data gave rise to false positive diagnoses in that a normal tooth could not be differentiated from its two infected neighbours. The semiconductor probe was found to provide more accurate diagnostic information than bone imaging.