Atypical femoral fracture with early PET/CT changes from denosumab for metastatic breast cancer and transition from denosumab to zoledronic acid.

Characterizing two subtypes of osteosarcoma using G2M checkpoint-related genes and revealing its immune landscape.

Denosumab therapy beyond 10 years: subsequent treatment and densitometric outcomes.

Effect of zoledronic acid on recurrent vertebral fractures after percutaneous vertebroplasty.

Bone modifying agents and multikinase inhibitors as treatments for chordoma: A TriNetX-based retrospective cohort study.

Hesperetin Modulates Osteoprogenitor Cells and Macrophages Under Zoledronic Acid and Inflammatory Stress

Superior Efficacy of Denosumab over Zoledronic Acid in Increasing Femoral Neck Bone Mineral Density in Osteoporosis Patients with Type 2 Diabetes Mellitus.

Bone-targeting single-atom nanozymes for treating breast cancer bone metastasis via the synergistic effect of mild photothermal and chemodynamic therapy.

The aim of this study is to evaluate the risk of osteonecrosis of the jaw in patients receiving osteoporosis treatment using C-terminal cross-linked telopeptide of type 1 collagen (CTX-1) values, to analyze follow-ups after drug holidays, and to compare treatment agents and other risk factors to determine the association with CTX-1 results. A total of 273 patients (266 female and 7 male) who received bisphosphonate and denosumab treatment for osteoporosis were included in this retrospective study. Sociodemographic characteristics, vitamin D levels, serum CTX-1 level, presence of diseases affecting CTX-1 levels, type of bisphosphonate, duration of use, presence of drug holidays, and duration of denosumab use (if any) were recorded. The effects of bisphosphonates and denosumab on CTX-1 levels were compared, and differences in the risk of osteonecrosis between them were evaluated. In this study, a meaningful association was not identified between serum CTX-1 levels and the measured vitamin D values (P = .232). Patients who underwent a drug holiday had significantly higher mean serum CTX-1 levels (266.2 Å} 175.1 pg/mL) compared to those without a drug holiday (199.9 Å} 138.5 pg/ mL; P = .009). Higher CTX-1 levels were observed in individuals receiving ibandronate and alendronate, whereas the lowest values were detected in patients treated with denosumab. Serum CTX-1 levels appeared unaffected by vitamin D. Although the denosumab group exhibited the highest risk of osteonecrosis, the difference compared to zoledronic acid was not statistically significant. These results suggest caution during jaw-related procedures and consideration of drug holidays when necessary. Cite this article as: Ergül EE, Laçin O, Kılıçaslan HÖ, et al. Evaluation of osteonecrosis risk using serum C-terminal cross-linked telopeptide of type 1 collagen (CTX-1) levels in osteoporotic patients: Effects of drug holidays and risk factors. Eurasian J Med. 2026, 58(1), 1104, doi:10.5152/eurasianjmed.2026.251104.

ABSTRACT Current treatments for osteoporosis and osteoporotic fractures, such as bisphosphonates and teriparatide, are limited by poor bone‐targeting and systemic toxicity. To address these issues, we developed a bone‐targeted nanodelivery platform (FPBE) by encapsulating β‐glycerophosphate (β‐GP) in a fluorinated polyethylenimine carrier. The platform was further functionalized with the E7 peptides to enhance the affinity for mesenchymal stem cells (MSCs) and improve bone marrow targeting. Biocompatibility and delivery efficiency were optimized by the degree of screening fluorination. Single‐cell RNA sequencing revealed that FPBE upregulates Wnt/β‐catenin, driving MSC osteogenic and chondrogenic differentiation to support regenerative processes. In postmenopausal mice, systemic FPBE increased bone mineral density (BMD), matching zoledronic acid levels with fewer side effects. In non‐human primates, FPBE increased BMD by 83.07% (males) and 55.92% (females), with serum analyses confirming its efficacy and safety. This nanoplatform—which delivers β‐GP to restore phosphate balance—provides a cost‐effective therapy for osteoporosis and osteoporotic fracture repair, with strong potential for clinical application.

IntroductionCalcium pyrophosphate dihydrate (CPPD) deposition in the joints is an inflammatory arthropathy known as pseudogout (PG). Rare cases of pseudogout associated with bisphosphonate therapy have been reported in the literature. Here, we present a patient with primary hyperparathyroidism (PHP) who developed pseudogout in the elbow joint following bisphosphonate use.Clinical CaseA 65-year-old female patient was evaluated due to hypercalcemia and diagnosed with primary hyperparathyroidism. No pathological focus was detected in ultrasonography and scintigraphy. Because of persistently high calcium levels and osteoporosis on bone densitometry, intravenous zoledronic acid (ZA) was administered. Three days after ZA treatment, the patient developed nausea and diffuse body pain. Laboratory evaluation revealed elevated creatinine levels, and she was admitted to the hospital with a preliminary diagnosis of acute kidney injury (AKI). On the third day of hospitalization, she developed pain, swelling, limited motion, and increased temperature in the right elbow. Since septic arthritis could not be excluded after orthopedic consultation, joint irrigation was performed. However, her complaints persisted, and joint culture revealed no bacterial growth. The patient was then evaluated by rheumatology, and pseudogout was considered. Systemic steroid therapy was initiated, leading to significant improvement in her symptoms.ConclusionAlthough bisphosphonates such as zoledronic acid (ZA) have an important role in the treatment of osteoporosis, potential complications should be kept in mind. In this case, the patient’s PHP, age, significant hypercalcemia at admission, and the rapid decrease in calcium levels after ZA treatment were predisposing factors for a PG attack. Pseudogout following ZA treatment is a rare complication reported in the literature.Table 1:Laboratory Parameters Before ZA, During AKI, and After Treatment

IntroductionPrimary hyperparathyroidism is usually caused by parathyroid adenomas, however atypical tumors are rare. Brown tumors can occur from excessive parathyroid hormone release, which increases osteoclastic bone resorption. Although rare, atypical parathyroid tumors can cause such lesions. An unusual parathyroid tumor with a brown tumor is shown here.Clinical CaseA 57-year-old woman presented to the orthopedics clinic with complaints of left hip pain. Imaging revealed a mass in the left acetabulum. Laboratory tests suggested primary hyperparathyroidism, and she was referred to endocrinology with a suspected brown tumor.Left hip pain had been present for 1.5 years, with recent worsening, causing difficulty in walking. Her medical history included percutaneous nephrolithotripsy for nephrolithiasis. Physical examination revealed painful and restricted movements of the left hip. Laboratory investigations demonstrated: calcium 13.2 mg/dL (8.8–10.6), phosphorus 2.2 mg/dL (2.5–4.5), PTH 883 ng/L (15–65), 25-OH vitamin D 35.2 μg/L, creatinine 1.05 mg/dL (0–1.2), TSH 0.8 mUI/L (0.48–4.81), and 24-hour urinary calcium 312 mg/day (0–300).Neck ultrasonography showed a 30x15 mm hypoechoic solid nodule posterior to the left thyroid lobe, suggestive of a parathyroid adenoma, along with additional hypoechoic solid nodules measuring 25 x 10 mm at the left lobe–isthmus junction and 17x10 mm within the left lobe, which were evaluated as thyroid nodules. Parathyroid scintigraphy confirmed the suspected parathyroid lesion. Thyroid scintigraphy showed that the nodules in the left lobe had a hyperfunctioning pattern. Pelvic MRI revealed a heterogeneous mass measuring 8x5 cm, eroding almost the entire acetabulum. Bone mineral densitometry indicated severe osteoporosis (L1–L4 T-score: –3.9; femoral neck T-score: –4.2). Ultrasound showed multiple calculi in the lower pole of the left kidney, the largest 5 mm.The patient was hospitalized, started on intravenous hydration, and given zoledronic acid. She then underwent left hemithyroidectomy and left inferior parathyroidectomy. Histopathological examination of the thyroid specimen revealed follicular nodular disease. The parathyroid specimen showed irregular parathyroid parenchyma with nodular hyperplasia, and the differential diagnosis included atypical parathyroid tumor and prior biopsy tract changes. However, the patient had no history of invasive neck procedures.Postoperatively, serum calcium and PTH normalized. The patient was closely monitored for atypical parathyroid tumor, and orthopedic follow-up was planned for the brown tumor.ConclusionThis case shows a rare presentation of an atypical parathyroid tumor with a destructive brown tumor in the acetabulum. Clinicians should strongly suspect primary hyperparathyroidism in patients with unexplained osteolytic lesions, especially if labs show hypercalcemia and high PTH.

IntroductionSuccessful treatment of Cushing disease and decrease of cortisol level may be associated with reactivation of the immune system and enhanced risk of onset of various autoimmune diseases.Material-MethodsClinical case of Cushing's disease in combination with primary hyperparathyroidism and further development of Graves’ disease.Clinical CaseFemale patient K., at aged 52 reported facial plethora (matronism), weight gain of 10 kg, striae, hypertension up to 200/130 mm Hg, a height decrease of -4 cm. Cushing's disease was confirmed based on appropriate laboratory tests and pituitary adenoma on MRI. A densitometry revealed a BMD decrease in lumbar spine (T-score -3.2 SD) and the proximal femur (T-score -1.7 SD). Primary hyperparathyroidism was also identified: mild hypercalcemia, parathyroid hormone 78 pg/mL (11-62), an adenoma of the left inferior parathyroid gland was found. Patient had 2 components of MEN 1 syndrome (pituitary adenoma and primary hyperparathyroidism), genetic analysis of MENIN was performed—no mutations were identified. The first stage of treatment was pituitary adenomectomy (histology: pituitary adenoma with nuclear polymorphism). In the postoperative period, secondary hypocortisolism and secondary hypothyroidism developed. Therapy with hydrocortisone and levothyroxine as well as bisphosphonates was initiated – with a positive effect. During observation period 12 months after the adenomectomy, the patient's free T4 level gradually increased. Levothyroxine was discontinued, without treatment free T4 was 40 pmol/l (9-19.1), and level TSH receptor antibodies was highly increased. An ultrasound examination showed diffuse enlargement of the thyroid gland with enhanced vascularization and the adenoma of the left inferior parathyroid gland. Thus thyroidectomy and left parathyroid adenomectomy were performed, and hormonal replacement therapy was adjusted (levothyroxine, hydrocortisone). Cholecalciferol, calcium carbonate, zoledronic acid were initiated for osteoporosis.ConclusionThe patient with Cushing's disease had coexisted primary hyperparathyroidism that worsened the patient's condition and exacerbated bone loss. After resolution of hypercortisolism, hyperthyroidism due to primary autoimmune thyroid disease developed in addition to the secondary postoperative hypothyroidism. Careful monitoring and a multidisciplinary approach led to the successful compensation of this patient's complex condition.

Paget's disease of bone (PDB) is a non-malignant skeletal disease that has become rare in recent decades. It is characterized by disorganized bone remodeling. Although its presentation varies worldwide, it is infrequently reported in Africans. To our knowledge, this is the first case series of PDB reported from Morocco, highlighting clinical and imaging features in a North African population. A retrospective case series and a literature review. Seven patients were identified during an 8-year period and diagnosed with Paget's disease of bone. Demographic profiles, clinical presentations, laboratory tests, imaging features and therapeutic approaches were collected and analyzed. The mean age of the seven patients (4 women and 3 men) at disease diagnosis was 60.5. The most affected sites were the spine and the skull. One patient had a monostotic form. Neurological complications were observed in three patients, including blindness due to optic nerve compression and profound hearing loss requiring cochlear implantation. One patient had concurrent bladder cancer, making the differential diagnosis challenging. Six patients had vitamin D deficiency or insufficiency. All patients received intravenous zoledronic acid, with significant clinical and biochemical improvement in the majority of cases. No malignant transformation was observed during follow-up. In this Moroccan series, incidental diagnosis was common and skull/spine involvement predominated, consistent with prior literature. The severity of neurological complications highlights the importance of early recognition and prompt metabolic management in comparable settings. Key Points • Clinical spectrum of Paget's disease of bone in a North African population. • Neurological complications and sensory impairments in Paget's disease. • Imaging features including a "cotton wool" appearance and diagnostic challenges. • Therapeutic outcomes of intravenous zoledronic acid in Paget's disease.

IntroductionParathyroid carcinoma is a rare endocrine disorder usually presented as severe primary hyperparathyroidism and skeletal complications. We present a case report of 52-year-old woman complaining from right arm pain, polyarthralgia and malaise. Work-up revealed right humeral mass later diagnosed as Brown tumor. On further assessment, she was having overt hypercalcemia, high parathyroid hormone (PTH), severe osteoporosis, and large left parathyroid mass. After controlling her medical situation conservatively, surgical resection of the parathyroid mass was done successfully and atypical parathyroid carcinoma confirmed. This case highlights the implications of early detection of severe hyperparathyroidism manifestations and the diagnostic obstacles in distinguishing benign from malignant parathyroid disease.Parathyroid carcinoma is very rare and accounts for less than 1% of cases of primary hyperthyroidism (1). It presents severe symptoms such as severe hypercalcemia, kidney stones, and skeletal manifestations ranging from osteitis fibrosa cystica to brown tumor (2). This is a rare case of parathyroid carcinoma presented as a brown tumor of the humerus, encouraging the urge for holistic endocrine evaluation in such an issue.Clinical CaseA 52-year-old woman presented with right arm pain, polyarthralgia, and fatigue. Enlarging right humerus mass biopsied and revealed a brown tumor. There was no nephrolithiasis or gastro-intestinal manifestations.Physical examination: a thin built, depressed, pallor woman with non-specific dysmorphic facial features.Laboratory results:Calcium: 14.5 mg\\dl, phosphate 1.83 mg\\dl, PTH 510.4 ng\\ml, vitamin D (25-OH) 30.85ng\\ml, creatinine 0.8 mg\\dl, creatinine clearance 68 mL/min/1.73m2, Hb=11.1gm\\dl, ESR 15 mm\\hr.Second sample blood advocate PTH markedly increased to 1406.1ng\\ml, Calcium 14.2 mg\\dl, PO42 1.59 mg\\dl.Imaging: neck ultrasound revealed a hypoechoic mass behind the left lobe measure 40x36 mm without dot of foci. Neck and chest CT scan localized 42x36x26 mm hyperdense enhancing lesion inferior to left thyroid lobe, multiple lytic bone lesions in ribs and osteosclerosis at D8 vertebra.DXA scans show severe osteoporosis with T score: -5.1 (L-Spine), -4.3 (femoral neck), -8.6 (Left radius).Medical treatment initiated to control the high calcium level and manage severe osteoporosis by hydration, starting zoledronic acid infusion protocol and preparing the patient for surgery. Neck dissection with mass excision was done by expert surgeon leading to normalization of calcium (8.8mg\\dl) and a drop in PTH (221.2ng\\ml) was achieved. Atypical parathyroid carcinoma with lympho-vascular and muscle invasion was confirmed by histopathological report.ConclusionA rare occurrence of parathyroid carcinoma has to be suspected for a case with extensive bone lesions and excess parathyroid secretion. Endocrine evaluation is corner stone to plan for precise diagnosis and management.Table 1:biochemical data of the patient with parathyroid carcinoma pre- and post-operatively.

IntroductionPaget's disease of bone is a metabolic bone disorder characterized by abnormal bone remodeling and is often detected incidentally through elevated alkaline phosphatase (ALP) or pathological fractures. Presentation with severe hypocalcemia is unusual. Here, we describe a rare case of Paget's disease admitted to the emergency department with profound hypocalcemia and extensive cranial bone involvement.Clinical CaseA 64-year-old woman presented with progressive somnolence and speech difficulties. Neurological evaluation revealed disorientation with a Glasgow Coma Scale score of 11, frontal and temporal bone prominence, and increased head size. Cranial changes had gradually progressed over the previous four years, with hearing loss and recurrent headaches emerging during the last two years. Her vital signs were stable. Chvostek’s and Trousseau’s signs were positive. Arterial blood gas analysis revealed pH 7.39, bicarbonate (HCO₃⁻) 30 mmol/L, and ionized calcium 2.3 mg/dL. Brain CT and diffusion MRI excluded acute stroke and intracranial hemorrhage. ECG demonstrated a prolonged QT interval of 490 ms. Laboratory tests showed severe hypocalcemia (Ca: 4.1 mg/dL), low phosphorus (2.1 mg/dL), markedly elevated ALP (1550 U/L), low vitamin D (<5 ng/mL), elevated parathyroid hormone (PTH: 125 pg/mL), and reduced 24-hour urinary calcium excretion (32 mg/day). She was treated with intravenous calcium infusion together with magnesium, requiring 8–10 ampoules of calcium gluconate daily (≈0.74–0.93 g elemental calcium) to maintain normocalcemia. She also received 150,000 IU/week intramuscular cholecalciferol, and oral calcitriol was initiated at 0.5 mcg/day. Electrolytes and clinical status were monitored daily. Skull X-ray revealed mixed lytic and sclerotic lesions consistent with the classic “cotton wool” appearance. Bone scintigraphy showed diffuse cranial uptake, suggesting active-phase Paget’s disease. The maximal skull thickness measured 6 cm. Given the extensive cranial involvement and unusual biochemical presentation, clinical exome sequencing was performed, which did not reveal any germline variant to explain this presentation. By the 10th day of hospitalization, her oral intake had improved, and intravenous treatment was tapered. She was discharged after stabilization with a prescription including 40,000 IU/week of cholecalciferol, 3 g/day of oral calcium carbonate, and 365 mg/day of oral magnesium supplementation. At her 3-month follow-up, laboratory results were: PTH 40.7 pg/mL, creatinine 0.9 mg/dL, calcium 9.7 mg/dL, phosphorus 3.8 mg/dL, albumin 4.0 g/dL, magnesium 2.0 mg/dL, and ALP 1000 U/L. She received 5 mg intravenous zoledronic acid at that visit.ConclusionThis case illustrates a rare presentation of Paget’s disease with severe hypocalcemia and massive skull involvement. Although radiological findings were consistent with Paget’s disease of bone, other causes of cranial bone thickening, such as osteopetrosis, should be excluded.Figure 1:Lateral skull X-ray of a patient with Paget’s disease of bone, showing massive cranial involvement with mixed lytic and sclerotic changes, giving the classic “cotton wool” appearance. Table 1:Laboratory Findings and Treatment Timeline in Paget’s DiseaseLaboratory parameters at admission and after treatment in a patient with Paget’s disease presenting with profound hypocalcemia and massive skull involvement. The table also summarizes the therapeutic interventions administered during hospitalization and follow-up.

This study aimed to evaluate the effects of laser photobiomodulation (PBM) therapy in SaOs-2 osteosarcoma cells treated with zoledronic acid (ZA), a bisphosphonate, in vitro, mimicking a bisphosphonate-related osteonecrosis of the jaw (BRONJ) situation. Cells were treated with 100 μM ZA for 24 h and subjected to PBM using wavelengths of 660 nm and 808 nm at energy delivered of 1, 5, 10, and 20 J. After 24 h, metabolic activity, apoptosis, and BAX and BCL-2 gene expression were analyzed. Data were compared using one-way ANOVA followed by Tukey's post hoc test (p < 0.05). ZA significantly reduced metabolic activity (p < 0.05), an effect attenuated by PBM at 808 nm with 1 J, while BCL-2 expression increased with 1 J at 660 nm and with 1 J and 20 J at 808 nm. However, PBM did not reverse ZA-induced apoptosis. In conclusion, PBM modulated the response of SaOs-2 osteoblastic cells treated with ZA in a wavelength- and dose-dependent manner. PBM at 808 nm and 1 J stimulated cell metabolic activity and upregulated BCL-2 expression, suggesting a potential protective effect against ZA-induced cytotoxicity.

This review evaluates established risk factors, examines pathogenic mechanisms, determines optimal treatment durations, and proposes evidence-based management strategies for Osteoporosis to enhance clinical practice. Key risk factors include advanced age, Asian descent, prolonged Bisphosphonates therapy (exceeding 5years for alendronate or 3years for zoledronic acid) without drug holidays, and distinct femoral geometry. The underlying pathophysiology is primarily linked to excessive suppression of bone turnover, resulting in progressive microdamage accumulation. Current clinical guidelines suggest implementing Bisphosphonates treatment interruptions (1-3years for oral regimens; 3-5years for intravenous administration) in patients with moderate fracture risk (femoral neck T-score > -2.5). Importantly, denosumab withdrawal necessitates a transition to alternative therapies-typically Bisphosphonates or teriparatide-to mitigate rebound bone loss. For managing Atypical Femoral Fractures, teriparatide demonstrates efficacy in promoting healing of active lesions, whereas intramedullary nailing represents the gold standard for complete fractures or high-risk incomplete fractures. Atypical Femoral Fractures management requires balancing Anti-Resorptive benefits against risks via individualized treatment, timely drug holidays, and rapid transition to bone-forming agents post-denosumab. Prophylactic surgery benefits high-risk fractures. Future research should elucidate denosumab's mechanisms and develop targeted therapies.

Precision medicine has transformed many areas in oncology. However, it remains largely unexplored in metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), where there is a need for further innovative therapies. To evaluate individual tumor responses to different agents, we have established a standardized personalized drug screening and risk assessment platform utilizing patient-derived GEP-NEN primary cultures (n=23, 16/23 from metastatic tumors, n=12 small intestinal neuroendocrine tumors [siNETs], n=10 pancreatic NETs [pNETs], n=1 neuroendocrine carcinoma [NEC]). We assessed primary culture cell viability, performed signaling pathway analysis by Automated Western blotting and immunohistochemically evaluated tumor composition. Systematic drug testing of 27 agents including signaling inhibitors (i) (mTORi everolimus, tyrosine kinase inhibitors cabozantinib/sunitinib, AKTi capivasertib, PI3Ki alpelisib, CDK4/6i ribociclib), DNA damage response inhibitors (PARPi niraparib, WEE1i adavosertib, ATRi berzosertib), chemotherapeutics (temozolomide, 5-fluorouracil, lurbinectedin), drug repurposed agents (zoledronic acid) and a personalized risk assessment (GLP-2 analog teduglutide, GLP-1 analog semaglutide, sex hormones) was performed. We demonstrated significant group effects and individualized responsiveness/resistance data. We identified differences in drug response between pNETs/siNETs and between GEP-NETs/GEP-NEC, respectively. We provide novel data on the efficacy of putative and established therapies in patient-derived GEP-NEN primary cultures. Our standardized platform for personalized drug screening and risk assessment in GEP-NEN primary cultures enables prediction of individual tumor treatment response in this orphan disease.

Adrenal insufficiency (AI) is characterized by inadequate steroid hormone production and is frequently a consequence of hypopituitarism, which is also associated with increased risk of osteoporosis due to deficiencies in growth hormone, gonadotropins, and other pituitary hormones. Zoledronic acid (ZA), a widely used bisphosphonate, is associated with acute phase reaction (APR) that may trigger adrenal crisis in susceptible individuals. We describe two patients with hypopituitarism and osteoporosis who developed adrenal crisis shortly after their first ZA infusion, despite stable physiological steroid replacement and acetaminophen prophylaxis. One presented with hypotension and shock within 24 h, the other with hypotension, severe hyponatremia, and seizures at 48 h. Both recovered after high‐dose glucocorticoids and were later switched to denosumab without complications. These cases highlight the potential for adrenal crisis in patients with central AI receiving ZA and suggest that standard prophylaxis may be insufficient. Alternative therapies and enhanced precautions may be warranted in this vulnerable population.