Effect of Bisphosphonates on Skeletal Related Events in Long Bone Metastases of Renal Cell Carcinoma: A Systematic Review.

Bone metastases (BMs) in patients with renal cell carcinoma (RCC) are lytic lesions which are prone to skeletal related events (SREs) such as (pending) pathological fractures or bone pain requiring radiotherapy or surgery. The aim of this review is to assess whether the use of bisphosphonates in patients with RCC and BMs in the long bones results in reduced SRE rate. A systematic review of literature was conducted, using PubMed, Embase, Medline, Web of Science, Cochrane, and Google Scholar (date 1971 till June 2021). All clinical studies on bisphosphonates in patients with RCC and BMs in long bones were retrieved. Primary outcome measure was SRE rate of BMs in long bones. Secondary outcome was fracture rate of BMs in long bones. Fourteen relevant articles were selected. Bisphosphonates reduced the mean skeletal morbidity rate by 0.4-0.95 SREs/year and had a pooled SRE rate of 38.3% (95% confidence interval [CI] 28.4%-49.3%). When bisphosphonates were added to radiotherapy the pooled SRE rate was 18.4% (95% CI, 10.5%-30.3%). In addition, pooled effect sizes showed a significant SRE risk reduction (RR 0.45, 95% CI, 0.24-0.85) in the bisphosphonates combined with radiotherapy group. There was limited reported data on rate of pathological fractures. In general, bisphosphonates reduce the SRE rate in RCC patients with BMs. The level of evidence for the effect of bisphosphonates on the rate of pathological fractures in patients with long BMs of RCC is low.

Case report: Complete remission of bone metastasis from renal cell carcinoma in histopathological examination after treatment with immune checkpoint inhibitors.

Recently, the prognosis of metastatic renal cell carcinoma (mRCC) has improved owing to the development of immunotherapy using immune checkpoint inhibitors (ICIs). However, there have been few studies on the therapeutic effect of ICIs in bone metastases from renal cell carcinoma (RCC). We report a case in which pulmonary and humeral metastases from RCC were significantly ameliorated using ICIs, while surgery for a pathological fracture of the humerus significantly improved the patient's quality of life (QoL). A 70-year-old man who underwent a left nephrectomy for RCC developed multiple pulmonary metastases and humeral metastasis with a pathological fracture one year after surgery, and combined treatment with nivolumab and ipilimumab was initiated. After four courses of ICI treatment, multiple pulmonary metastases had almost disappeared, and the tumor at the fracture site had shrunk remarkably. However, the shoulder joint function had decreased due to the fracture, worsening his QoL. Therefore, he underwent surgery and returned to normal daily life one month after. Postoperative histopathological examination of bone and soft tissue at the fracture site revealed no malignancy. To our knowledge, this is the first case report of complete remission of bone metastasis of RCC based on histopathological examination with ICI treatment.

Avoiding complications in percutaneous osteoplasty.

Percutaneous osteoplasty techniques include cement injection either solely performed or in combination to hardware such as cannulated screws, peek implants or other metallic hardware including micro-needles and Kirschner wires. Depending on bone and local forces applied, fracture and osseous defect characteristics as well as symptoms and operator's preference percutaneous osteoplasty techniques include cementoplasty, fixation by internal cemented screw and augmented osteoplasty. Literature data support efficacy and safety of these techniques, focusing mainly on the minimal invasive nature of these approaches along with minimum overall morbidity and mortality and an impressive pain reduction effect. Percutaneous osteoplasty techniques in the peripheral skeleton are indicated for pain palliation or for prevention of impeding pathologic fractures. Although safe, osteoplasty techniques are not without risk of complications and adverse events. Complications are classified based either upon clinical impact or timing of occurrence; complications' reviewing and grading should be performed on terms of a uniform and accurate reproducible and validated categorization system. Significant factors for avoiding complications in percutaneous osteoplasty techniques include proper training, patient- and lesion-tailored approach, high-quality imaging guidance, sterility as well as appropriate selection of technique and materials. The present article reports the possible complications of percutaneous osteoplasty techniques and reviews the prerequisites necessary for avoiding and managing these adverse events.

The use of denosumab in the setting of acute pathological fracture through giant cell tumour of bone.

BACKGROUND: Denosumab (XgevaTM) is a fully human antibody to RANK-Ligand, an important signal mediator in the pathogenesis of giant cell tumour of bone (GCTB). The use of denosumab in the treatment of GCTB has changed the way in which these tumours are managed over the past years. CASE PRESENTATION: Described is the case of an acute fracture through a GCTB of the distal radius of a fit and well 32-year-old, non-smoking, female patient following a simple fall onto her outstretched, dominant hand. The aim was to enable joint sparing management for the patient, as opposed to an acute fusion procedure of the carpus. The patient underwent percutaneous k-wire fixation with application of plaster and immediate commencement with denosumab to halt the activity of the GCTB. Bone healing was rapid; plaster and k-wires were removed after 6 weeks. At 6 months denosumab, was ceased and an open curettage and grafting procedure of the tumour bed was undertaken (using MIIG X3, Wright Medical, aqueous calcium sulphate as graft material). CONCLUSIONS: The use of denosumab in the acute setting of pathological fracture through giant cell tumour of bone allowing joint salvage has not been previously described. The treatment was well tolerated and functional outcomes are excellent, with very promising 4-year follow-up. This novel approach may allow for more joint sparing strategies in the future for other patients in this difficult situation. Further cases will need to be gathered to establish this technique as a suitable treatment pathway.

[Osteoporosis and chronic kidney disease: review and new therapeutic strategies].

Osteoporosis affects a segment of the population in which Chronic Kidney Disease is also greatly represented. Nephropathic patients may present peculiar biochemical abnormalities related to Chronic Kidney Disease, defining the Mineral and Bone Disorder. This kind of anomalies, in the worst scenarios, configure the typical histomorphology patterns of Renal Osteodystrophy. Scientific Societies of Endocrinology have established therapy guidelines for patients with osteoporosis only based on the glomerular filtration rate and recommend avoiding the use of some drugs for the more advanced classes of nephropathy. However, there is no clear therapeutic approach for patients with advanced nephropathy and bone abnormalities. In this paper we propose a systematic review of the literature and present our proposal for managing patients with advanced nephropathy, based on eGFR and on presence of Mineral and Bone Disorder.

Effects of combined menaquinone-4 and PTH1-34 treatment on osetogenesis and angiogenesis in calvarial defect in osteopenic rats.

PURPOSE: The aim of this study was to evaluate the effect of combining human parathyroid hormone (1-34) (PTH1-34; PTH) and menaquinone-4 (MK-4) on calvarial bone defect repair in osteopenic rats. METHODS: Fourteen week olds were subject to craniotomy for the establishment of osteopenic animal models fed through a chronically low-protein diet. After that, critical calvarial defect model was established and all rats were randomly divided into four groups: sham, MK-4, PTH, and PTH + MK-4. The animals received MK-4 (30 mg/kg/day), PTH1-34 (60 µg/kg, three times a week), or PTH1-34 (60 µg/kg, three times a week) plus MK-4 (30 mg/kg/day) for 8 weeks, respectively. Serum γ-carboxylated osteocalcin (Gla-OC) levels, histological and immunofluorescent labeling were employed to evaluate the bone formation and mineralization in calvarial bone defect. In addition, Microfil perfusion, immunohistochemical, and micro-CT suggested enhanced angiogenesis and bone formation in calvarial bone healing. RESULTS: In this study, treatment with either PTH1-34 or MK-4 promoted bone formation and vascular formation in calvarial bone defects compared with the sham group. In addition, combined treatment of PTH1-34 plus MK-4 increased serum level of Gla-OC, improved vascular number and vascular density, and enhanced bone formation in calvarial bone defect in osteopenic conditions as compared with monotherapy. CONCLUSIONS: In summary, this study indicated that PTH1-34 plus MK-4 combination therapy accelerated bone formation and angiogenesis in calvarial bone defects in presence of osteopenia.

Teriparatide for treatment of patients with bisphosphonate-associated atypical fracture of the femur.

The Fracture Improvement with Teriparatide (Fix-IT) study randomized 13 women with an atypical femur fracture to immediate vs delayed teriparatide therapy; all were followed for 12 months. Results suggested a trend for superior healing and lesser bone mineral density declines in the immediate vs delayed group with no differences in adverse events. PURPOSE: Little clinical data are available on the use of teriparatide for the treatment of bisphosphonate-associated atypical femur fractures (AFF). The goal of the Fix-IT study was to determine if immediate therapy with teriparatide was superior for fracture healing after an AFF compared to a 6-month delay in teriparatide therapy. METHODS: This randomized pilot clinical trial included 13 women with an AFF who were randomized to immediate teriparatide vs a delay of 6 months. All were followed for 12 months on teriparatide. The primary outcomes included individual and composite measures of radiologic bone healing (scored 1 point [no healing] to 4 points [complete healing]) at 6 and 12 months. Secondary outcomes included bone mineral density of the unfractured contralateral hip, spine, 1/3 distal radius, and adverse events. RESULTS: We found there was a trend for superior healing with the composite score (12.6 vs 11.2 at 6 months and 15.4 vs 13.2 at 12 months), and lesser bone mineral density declines at the 1/3 distal radius (12-month change - 1.9 vs - 6.1%) in the immediate vs the delayed group. There were no differences in adverse events. There was one implant failure in the delayed group. CONCLUSIONS: There is a preliminary signal for greater improvements with immediate teriparatide therapy vs delayed therapy. However, because an AFF is a rare event, and only a small number of patients were included, the results must be interpreted with caution.

Management of atypical femoral fracture in a patient with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a generalised connective tissue disorder associated with low bone mass, bone fragility and increased susceptibility to fractures. First-line treatment to improve bone mineral density (BMD) is usually with bisphosphonates but long-term usage has been associated with uncommon complications such as atypical femoral fractures (AFF). Treatment with teriparatide in this situation has been reported with positive outcomes. However, choice of treatment after 2 years of teriparatide has not been well studied or reported. We describe a patient with OI treated with bisphosphonates for 9 years, who then suffered a spontaneous AFF, was subsequently started on teriparatide for 2 years followed by 6 monthly Denosumab. 1 year post-treatment with Denosumab, there was significant improvement in BMD, good fracture healing and no new fractures. This case highlights the potential use of denosumab following 2 years of teriparatide treatment in patients with OI with AFF.

Pathologic fracture of the thoracic spine in a male master ultra-marathoner due to the combination of a vertebral hemangioma and osteopenia.

Vertebral hemangiomas are the most common benign vertebral neoplasms and are generally asymptomatic. In the present study, we report the case of a 52-year-old male master ultra-marathoner suffering from a pathologic fracture of the thoracic spine due to a vertebral hemangioma. A further examination in the athlete revealed an accompanying osteopenia, which was most likely due to a deficiency in both vitamin D and testosterone. The treatment of the fracture consisted of percutaneous vertebroplasty. Shortly after the operation the athlete was able to continue running. The most likely reason for the pathologic fracture of the vertebral body was the combination of the vertebral hemangioma and osteopenia. The further treatment consisted of supplementation of both vitamin D and testosterone. Athletes and physicians should be aware that male master ultra-marathoners older than 50 years might suffer from osteopenia, where a deficiency in vitamin D and testosterone could be contributing factors for osteopenia development in general.

Low-trauma fractures without osteoporosis.

In clinical practice, areal bone mineral density (aBMD) is usually measured using dual-energy X-ray absorptiometry (DXA) to assess bone status in patients with or without osteoporotic fracture. As BMD has a Gaussian distribution, it is difficult to define a cutoff for osteoporosis diagnosis. Based on epidemiological considerations, WHO defined a DXA-based osteoporosis diagnosis with a T-score <-2.5. However, the majority of individuals who have low-trauma fractures do not have osteoporosis with DXA (i.e., T-score <-2.5), and some of them have no decreased BMD at all. Some medical conditions (spondyloarthropathies, chronic kidney disease and mineral bone disorder, diabetes, obesity) or drugs (glucocorticoids, aromatase inhibitors) are more prone to cause fractures with subnormal BMD. In the situation of fragility fractures with subnormal or normal BMD, clinicians face a difficulty as almost all the pharmacologic treatments have proved their efficacy in patients with low BMD. However, some data are available in post hoc analyses in patients with T score >-2. Overall, in patients with a previous fragility fracture (especially vertebra or hip), treatments appear to be effective. Thus, the authors recommend treating some patients with a major fragility fracture even if areal BMD T score is above -2.5.

Bone microarchitecture deteriorations and a fragility fracture in a patient with beta and alpha heterozygous thalassemia: a case report.

To date there are few studies that have investigated bone mineral density (BMD) and markers of bone metabolism in patients with thalassemia minor form. None of the previous trials presented bone structure analysis in the patient populations. We present the case of a 24-year-old Turkish woman with heterozygous beta and alpha thalassemia who sustained a low-trauma fracture of the inferior pubic ramus. Despite normal markers of bone metabolism, the dual X­ray absorptiometry (DXA) showed decreased areal bone mineral density. Furthermore, severely reduced bone structure parameters and reduced volumetric bone mineral density was assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT). Due to these diagnostic findings at time of peak bone mass, an osteoanabolic therapy with teriparatide for 24 months was initiated. The findings concerning BMD and bone structure in this patient can be seen as caused by the beta and alpha thalassemia.

Osteogenesis imperfecta type III and hypogonadotropic hypogonadism result in severe bone loss: a case report.

We present the case of a 33-year-old male patient with multiple fractures and typical radiographical and clinical characteristics of osteogenesis imperfecta (OI) type III. Furthermore, the patient has suffered from hypogonadotropic hypogonadism since childhood. On the basis of antiresorptive therapy, no further fractures occurred within several years. Recently, recurrent nontraumatic fractures without bone healing were observed. Decreased bone mineral density was assessed by dual X-ray absorptiometry (DXA). High-resolution peripheral quantitative computed tomography (HR-pQCT) showed impaired trabecular bone structure. Due to recurrent fragility fractures and severe deterioration of bone structure, an osteoanabolic treatment with teriparatide was initiated to potentially stimulate fracture healing and to increase bone formation.

Burden of skeletal-related events in prostate cancer: unmet need in pain improvement.

PURPOSE: Up to 75% of patients with prostate cancer experience metastatic bone disease, which leads to an increased risk for skeletal-related events (SREs) including pathological bone fracture, spinal cord compression, and hypercalcemia of malignancy. Our objective was to systematically review the literature on the impact of SREs on quality of life (QOL), morbidity, and survival with a primary focus on the impact of SREs on pain in prostate cancer patients. METHODS: We searched PubMed, limiting to peer-reviewed English-language human studies published in 2000-2010. The search was based on the US Food and Drug Administration and European Medicines Agency definition of an SRE, which includes pathologic fracture, spinal cord compression (SCC), hypercalcemia of malignancy, and radiotherapy or surgery to bone resulting from severe bone pain. RESULTS: A total of 209 articles were screened, of which 173 were excluded, and 36 were included in this review. Patients with SREs had more pain and worse survival compared with no SREs. Pathologic bone fractures worsened QOL and were associated with shorter survival. Radiation therapy of SCC alleviated pain and improved morbidity. SCC was associated with decreases in patient survival. Radiation therapy and surgery to bone improved pain. CONCLUSIONS: Specific SREs are associated with worse outcomes, including increased pain, poorer QOL, morbidity, and survival. Treatment of SREs is associated with improved pain, although there remains a need for more effective treatment of SREs in prostate cancer patients.

Bone-targeting radiopharmaceuticals for the treatment of bone-metastatic castration-resistant prostate cancer: exploring the implications of new data.

BACKGROUND: Clinical features of patients with castration-resistant prostate cancer (CRPC) are characterized by a high incidence of bone metastases, which are associated with impairment of quality of life, pain, skeletal-related events (SREs), and a negative impact on prognosis. Advances in the understanding of cancer cell-bone stroma interactions and molecular mechanisms have recently permitted the development of new agents. PURPOSE: We review the merits, applications, and limitations of emerging data sets on bone-metastatic CRPC with a focus on radium-223, an α-emitting radiopharmaceutical, and its use in therapy for this disease. METHODS: References for this review were identified through searches of PubMed and Medline databases, and only papers published in English were considered. Related links in the databases were reviewed, along with relevant published guidelines, recently published abstracts from major medical meetings, and transcripts from a recent round table of clinical investigators. RESULTS: Prior to radium-223, available bone-targeted therapies demonstrated the ability to delay SREs and palliate bone pain in patients with metastatic CRPC but without evidence of improvement in overall survival (OS). In a randomized controlled phase III trial, radium-223 demonstrated the ability to improve OS and delay SREs in docetaxel-pretreated or docetaxel-unfit men with symptomatic bone-metastatic CRPC and was not associated with significantly more grade 3 or 4 adverse events than placebo. CONCLUSION: Radium-223 has a targeted effect on bone metastases in CRPC and has an important role in docetaxel-pretreated or docetaxel-unfit men with symptomatic bone-metastatic CRPC.

Use of bisphosphonates in orthopedic surgery: pearls and pitfalls.

Bisphosphonates are medications known to decrease bone resorption by inhibiting osteoclastic activity. They are the first-line therapy for the treatment of osteoporosis because a significant body of literature has proved their efficacy in reducing the risk of fracture in the hip, spine and other nonvertebral osseous sites. In addition, the use of bisphosphonates has significantly decreased morbidity and increased survival, and they have also proved to be cost-effective. Unexpected adverse effects have been reported recently, but the benefit of bisphosphonates use outweighs the risks. This article reviews the current use of bisphosphonates in orthopedic surgery.

[Acute osteomyelitis of the clavicle in the newborn infant: a case report]. / L'ostéomyélite aiguë de la clavicule chez le nouveau-né : à propos d'un cas.

Acute osteomyelitis of the clavicle accounts for less than 3% of osteomyelitis cases, with its usual location in the middle third. It may be hematogenous, due to contiguity, or secondary to catheterization of the subclavian vein or neck surgery. The diagnosis is often delayed, and clinical symptoms may simulate obstetric brachial plexus palsy in young children. We report a new case of osteomyelitis of the clavicle in a 30-day-old newborn.

Pathological fractures in paediatric patients with inflammatory bowel disease.

UNLABELLED: Paediatric inflammatory bowel disease (IBD), especially Crohn's disease (CD), is commonly associated with poor skeletal health, related to the direct effects of chronic inflammation, prolonged use of glucocorticoid (GC), poor nutrition, delayed puberty and low muscle mass. Low bone mineral density is commonly reported, although the prevalence of long bone fractures may not be increased in these patients. Emerging evidence however suggests that there may be an increased risk of vertebral fractures (VFs) in this group. VFs presenting at diagnosis of paediatric CD, prior to any GC exposure, have been reported, highlighting the deleterious effect of inflammation on skeletal health. This paper reviews the published literature on pathophysiology of skeletal morbidity and fractures in paediatric IBD, illustrated with a new case report of multiple VFs in a prepubertal girl with CD, soon after diagnosis, who received minimal amounts of oral GC. Optimising control of disease, addressing vitamin D deficiency, encouraging physical activity and ensuring normal growth and pubertal progression are paramount to management of bone health in these patients. Despite the lack of evidence, there may be a place for bisphosphonate treatment, especially in the presence of symptomatic pathological fractures, but this requires close monitoring by clinicians with expertise in paediatric bone health. CONCLUSION: Chronic inflammation mediated by pro-inflammatory cytokines may have adverse effects on skeletal health in paediatric patients with IBD. The risk of vertebral fractures may be increased, even without exposure to glucocorticoid. Clinical monitoring of these patients requires careful attention to the various factors that impact on bone health.

The effect of Amifostine prophylaxis on bone densitometry, biomechanical strength and union in mandibular pathologic fracture repair.

BACKGROUND: Pathologic fractures (Fx) of the mandibles are severely debilitating consequences of radiation (XRT) in the treatment of craniofacial malignancy. We have previously demonstrated Amifostine's effect (AMF) in the remediation of radiation-induced cellular damage. We posit that AMF prophylaxis will preserve bone strength and drastically reverse radiotherapy-induced non-union in a murine mandibular model of pathologic fracture repair. MATERIALS AND METHODS: Twenty-nine rats were randomized into 3 groups: Fx, XRT/Fx, and AMF/XRT/Fx. A fractionated human equivalent dose of radiation was delivered to the left hemimandibles of XRT/Fx and AMF/XRT/Fx. AMF/XRT/Fx was pre-treated with AMF. All groups underwent left mandibular osteotomy with external fixation and setting of a 2.1mm fracture gap post-operatively. Utilizing micro-computed tomography and biomechanical testing, the healed fracture was evaluated for strength. RESULTS: All radiomorphometrics and biomechanical properties were significantly diminished in XRT/Fx compared to both Fx and AMF/XRT/Fx. No difference was demonstrated between Fx and AMF/XRT/Fx in both outcomes. CONCLUSION: Our investigation establishes the significant and substantial capability of AMF prophylaxis to preserve and enhance bone union, quality and strength in the setting of human equivalent radiotherapy. Such novel discoveries establish the true potential to utilize pharmacotherapy to prevent and improve the treatment outcomes of radiation-induced late pathologic fractures.

Characterization of clinical course and usual care patterns in female metastatic breast cancer patients treated with zoledronic acid.

PURPOSE: To describe usual care received by women with bony metastatic breast cancer (ICD-9: 174.xx and 198.5) treated in a United States specialty cancer hospital, an Electronic Medical Record (EMR)-based retrospective review identified 111 deceased female breast cancer patients ≥18 years of age treated with zoledronic acid (ZOL). RESULTS: Baseline symptoms included bone pain/fracture (58.6%), breathing difficulties (24.3%), or mental status changes (11.7%). ZOL was started at/after metastatic diagnosis for 75.7% of women (N = 84), with average administration of 15.9 months (median 11.3). Nearly 20% required reduced ZOL doses, most (54.5%) due to impaired renal function; 61.3% discontinued ZOL due to patient death/disease progression. Adverse events were reported in 10.8%, while 0.9% (N = 1) had a documented osteonecrosis of the jaw. CONCLUSIONS: Initiation of palliative care should be considered early in patients with a history of metastatic breast cancer who report bone pain or other skeletal-related events.