Prevention and Treatment of Pathologic Femur Fractures: Evidence as of 2019.

This chapter is largely drawn from the recently published (2019) clinical practice guideline on the treatment of metastatic carcinoma and myeloma of the femur jointly produced by the Musculoskeletal Tumor Society, American Society for Radiation Oncology, and American Society of Clinical Oncology. Previous clinical practice guidelines on this topic broadly addressed the potential benefits of bone-targeted agents (eg, diphosphonates) on skeletal-related events, a broad term that encompasses pathologic fractures of any bone, need for surgery or radiation, and hypercalcemia. Guidelines on the use of palliative radiation therapy primarily focused on short-term pain control and long-term radiation-induced adverse effects. The starting goals of this guideline were twofold-focus on the femur, as fractures of the femur almost always require surgery and, when about the hip, dramatically alter patients' quality of life and, potentially, survival; and to address this topic in a multidisciplinary fashion that includes the insights of orthopaedic surgeons, along with radiation oncologists and medical oncologists. For many important clinical topics, there is a dearth of evidence, which will hopefully prompt researchers and funding agencies to help fill these evidentiary gaps.

Nanopatterning and Bioprinting in Orthopedic Surgery.

In part 1 of this article, the authors explore nanoscale modifications of the surfaces of biomaterials, which offer an exciting potential venue for the prevention of bacterial adhesion and growth. Despite advances in the design and manufacture of implants, infection remains an important and often devastating mode of failure. In part 2, additive technologies for tissue engineering, live cell printing (bioprinting), and tissue fabrication are briefly introduced. The similarities and differences between bioprinting and non-bio 3D-printing approaches and requirements are discussed, along with terminological definitions, current processes, requirements, and biomaterial and cell-type selection and sourcing.

Top five lesions that do not need referral to orthopedic oncology.

Patients with potential bone and soft tissue tumors can be challenging for orthopedic surgeons. Lesions that appear benign can still create anxiety for the clinician and patient. However, attention to a few key imaging and clinical findings is enough to correctly diagnose five of the most common bone and soft tissue lesions: lipoma, enchondroma, osteochondroma, nonossifying fibroma, and Paget disease. Accurate identification of these lesions should be within the scope of most orthopedic surgeons and, because most of these patients will not need surgical treatment, referral to orthopedic oncology will not typically be required.

Tumor localization and biochemical response to cure in tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare disorder of phosphate wasting due to fibroblast growth factor-23 (FGF23)-secreting tumors that are often difficult to locate. We present a systematic approach to tumor localization and postoperative biochemical changes in 31 subjects with TIO. All had failed either initial localization, or relocalization (in case of recurrence or metastases) at outside institutions. Functional imaging with ¹¹¹Indium-octreotide with single photon emission computed tomography (octreo-SPECT or SPECT/CT), and ¹8fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) were performed, followed by anatomic imaging (CT, MRI). Selective venous sampling (VS) was performed when multiple suspicious lesions were identified or high surgical risk was a concern. Tumors were localized in 20 of 31 subjects (64.5%). Nineteen of 20 subjects underwent octreo-SPECT imaging, and 16 of 20 FDG-PET/CT imaging. Eighteen of 19 (95%) were positive on octreo-SPECT, and 14 of 16 (88%) on FDG-PET/CT. Twelve of 20 subjects underwent VS; 10 of 12 (83%) were positive. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were as follows: sensitivity = 0.95, specificity = 0.64, PPV = 0.82, and NPV = 0.88 for octreo-SPECT; sensitivity = 0.88, specificity = 0.36, PPV = 0.62, and NPV = 0.50 for FDG-PET/CT. Fifteen subjects had their tumor resected at our institution, and were disease-free at last follow-up. Serum phosphorus returned to normal in all subjects within 1 to 5 days. In 10 subjects who were followed for at least 7 days postoperatively, intact FGF23 (iFGF23) decreased to near undetectable within hours and returned to the normal range within 5 days. C-terminal FGF23 (cFGF23) decreased immediately but remained elevated, yielding a markedly elevated cFGF23/iFGF23 ratio. Serum 1,25-dihydroxyvitamin D3 (1,25D) rose and exceeded the normal range. In this systematic approach to tumor localization in TIO, octreo-SPECT was more sensitive and specific, but in many cases FDG-PET/CT was complementary. VS can discriminate between multiple suspicious lesions and increase certainty prior to surgery. Sustained elevations in cFGF23 and 1,25D were observed, suggesting novel regulation of FGF23 processing and 1,25D generation.

Selective venous catheterization for the localization of phosphaturic mesenchymal tumors.

Tumor-induced osteomalacia (TIO) is characterized by renal phosphate wasting, hypophosphatemia, and aberrant vitamin D(3) metabolism and is caused by fibroblast growth factor 23 (FGF-23)-producing mesenchymal tumors, which are often difficult to locate. We investigated the utility of selective venous sampling in tumor localization. The primary endpoint was identification of the FGF-23 concentration ratio between the venous drainage of the tumor bed and the general circulation that was diagnostic of the location of an FGF-23-secreting tumor. Fourteen subjects underwent 15 sampling procedures after functional and anatomic imaging studies. Subjects fit into three imaging categories: no suspicious site, multiple sites, and single site (positive controls). FGF-23 levels were measured by ELISA. Suspicious tumors were resected for diagnosis, confirmation, and cure. In subjects with a positive venous sampling study and subsequent cure, a minimum ratio of 1.6 was diagnostic. In 7 of 14 subjects there was suggestive imaging, a diagnostic ratio, and an associated TIO tumor (true positive). Four of these required complicated resection procedures. In 4 of 14 subjects with no suspicious site on imaging studies, an FGF-23 diagnostic ratio was not detected (true negative). Biopsy or resection of a single lesion in 2 of 14 subjects with a diagnostic ratio failed to identify a TIO tumor (false positive). A diagnostic FGF-23 ratio was absent in 1 of 14 subjects whose tumor was a single highly suspicious lesion on imaging studies (false negative). These data yield a sensitivity of 0.87 [95% confidence interval (CI) 0.47-0.99] and a specificity of 0.71 (95% CI 0.29-0.96). Selective venous sampling for FGF-23 was particularly useful in subjects with multiple suspicious sites or an anatomically challenging planned resection but not in the absence of a suspicious lesion on imaging studies.

Metastatic carcinoma of the long bones.

Breast, prostate, renal, thyroid, and lung carcinomas commonly metastasize to bone. Managing skeletal metastatic disease can be complex. Pain is the most common presenting symptom and requires thorough radiographic and laboratory evaluation. If plain-film radiography is not sufficient for diagnosis, a bone scan may detect occult lesions. Patients with lytic skeletal metastases may be at risk for impending fracture. Destructive lesions in the proximal femur and hip area are particularly worrisome. High-risk patients require immediate referral to an orthopedic surgeon. Patients who are not at risk for impending fracture can be treated with a combination of radiotherapy and adjuvant drug therapy. Bisphosphonates diminish pain and prolong the time to significant skeletal complications.

Determination of the elimination half-life of fibroblast growth factor-23.

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic disease caused by mesenchymal tumors that secrete fibroblast growth factor-23 (FGF-23), a newly-described vitamin D and phosphate-regulating hormone. Surgical removal of the tumor, the ectopic source of circulating FGF-23, offers the opportunity to determine the elimination half-life of FGF-23. OBJECTIVE: The aim of the study was to determine the elimination half-life of FGF-23. PATIENTS/METHODS: The tumors were removed from three patients with TIO, and serum samples were taken every 30 min for up to 72 h after the operation. FGF-23 was measured by both a C-terminal/intact assay and an intact assay, and the elimination half-life was determined by one phase exponential decay methodology. SETTING: The Mark O. Hatfield Clinical Research Center of the National Institutes of Health, a tertiary referral clinical research center, was the setting for the study. RESULTS: The elimination life of FGF-23 as determined by C-terminal/intact and intact assays was 46 +/- 12 and 58 +/- 34 min, respectively. CONCLUSIONS: The plasma half-life of serum FGF-23 is in the range of 46-58 min.