•Pre-clinical and clinical data suggest RANKL inhibition to have antitumor effects.•Antitumor effects of RANKL inhibition are suggested to be both indirect and direct.•An immune mediated anti-tumor ...effect of RANKL inhibition is well conceivable.
At present, accumulating evidence suggests that inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL) does not only induce an increase in bone mass and strength, but also has anti-tumor effects. Denosumab, an antibody targeting RANKL, is used to treat osteoporosis and to prevent skeletal related events (SREs) in patients with bone metastases originating from solid tumors. However, expression of RANKL and its receptor activator of nuclear factor kappa-B (RANK) is not solely restricted to cells involved in homeostasis of the bone and RANKL-RANK signalling appears to play a substantial role in many other processes in the body like mammary physiology, mammary tumorigenesis and the immune system. In pre-clinical models, RANKL inhibition has been shown to reduce skeletal tumor burden and distant metastases as well as to decrease mammary carcinogenesis. Clinically, RANKL inhibition improves bone-metastasis free survival in patients with prostate cancer and disease-free survival in patients with breast cancer. In addition, RANKL treatment may form a preventative strategy in patients at high risk for malignancies of the breast. Current clinical studies are evaluating the effect of denosumab on survival, the immune system and other biomarkers into a greater extent. To that purpose, a systematic review of the literature was performed and a narrative review synthesized, describing the present pre-clinical and clinical evidence of an anti-tumor effect of RANKL inhibition and the potential role of the immune system as one of the underlying mechanisms.
Chronic nonbacterial osteomyelitis (CNO) is a rare, and impactful auto-inflammatory bone disease occurring in children and adults. Clinical care for CNO is challenging, as the condition lacks ...validated classification criteria and evidence-based therapies. This study aimed to map the current diagnostic and therapeutic practices for CNO in adults, as a first step towards a standardized disease definition and future consensus treatment plans.
A primary survey was spread among global rheumatological/bone networks and 57 experts as identified from literature (May 2022), covering terminology, diagnostic tools (clinical, radiological, biochemical) and treatment steps. A secondary survey (sent to primary survey responders in August 2022) further queried key diagnostic features, treatment motivations, disease activity and treatment response monitoring.
36 and 23 physicians completed the primary and secondary survey respectively. Diagnosis was mainly based on individual physician assessment, in which the combination of chronic relapsing-remitting bone pain with radiologically-proven osteitis/osteomyelitis, sclerosis, hyperostosis and increased isotope uptake on bone scintigraphy were reported indicative of CNO. Physicians appeared more likely to refer to the condition as synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome in the presence of joint and skin pathology. MRI was most frequently performed, and the preferred diagnostic test for 47%. X-rays were second-most frequently used, although considered least informative of all available tools. Typical imaging features reported were hyperostosis, osteitis, osteosclerosis, bone marrow edema, while degeneration, soft tissue calcification, and ankylosis were not regarded characteristic. Inflammation markers and bone markers were generally regarded unhelpful for diagnostic and monitoring purposes and physicians infrequently performed bone biopsies. Management strategies diverged, including indications for treatment, response monitoring and declaration of remission. Step-1 treatment consisted of non-steroidal anti-inflammatory drugs/COX-2 inhibitors (83%). Common step 2-3 treatments were pamidronate, methotrexate, and TNF-a-inhibition (anti-TNFα), the latter two regarded especially convenient to co-target extra-skeletal inflammation in SAPHO syndrome. Overall pamidronate and anti-TNFα and were considered the most effective treatments.
Following from our survey data, adult CNO is a broad and insufficiently characterized disease spectrum, including extra-osseous features. MRI is the favoured imaging diagnostic, and management strategies vary significantly. Overall, pamidronate and anti-TNFα are regarded most successful. The results lay out current practices for adult CNO, which may serve as backbone for a future consensus clinical guideline.
Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare genetic bone disease caused by a somatic mutation in the GNAS gene. Currently used bone turnover markers (BTMs) do not correlate with the ...clinical picture and are not useful to predict or monitor therapy success. This study assessed the correlation of RANKL, OPG, RANKL/OPG ratio, IL-6 and sclerostin with the classic BTMs alkaline phosphatase (ALP), procollagen type 1 propeptide (P1NP) and beta crosslaps (CTX), with pain, skeletal burden score (SBS) and response to bisphosphonate or denosumab treatment.
Ninety-six serum samples of adult patients >18 years of age with any subtype of FD/MAS were included from the biobank facility of the Leiden University Medical Center, Center for Bone Quality between 2015 and 2021. Standard laboratory assessments were assessed as part of usual care. The concentrations of potential biomarkers RANKL, OPG, sclerostin, IL-6 were analyzed. Data on FD/MAS subtype, age, pain, treatment history and treatment response were retrieved from the electronic patient files. Baseline characteristics were summarized by descriptive statistics. Correlations of the concentrations of the potential biomarkers with classic bone turnover markers, SBS and pain scores were cross-sectionally assessed by Spearman rank order correlation. Correction for multiple testing was performed by Benjamini and Hochberg False Discovery Rate. A sensitivity analyses was performed by excluding patients with SBS below 15 and patients using antiresorptive medication at the time of blood withdrawal or within the wash-out period. In patients treated with bisphosphonates or denosumab after blood withdrawal, pre-treatment concentrations were compared in patients with and without therapy response by Mann Whitney U test.
The median age of the patients was 41.2 (Q1-Q3 25.9–52.2) years, 62.5 % was female. Median SBS was 2.5 (Q1-Q3 0.5–7.8). RANKL level correlated weakly with ALP (Spearman rho 0.309, p = 0.004, n = 84), but not with P1NP or CTX. The RANKL/OPG ratio, OPG, IL-6 and sclerostin did not correlate with ALP, P1NP or CTX. None of the potential biomarkers correlated with SBS or pain. Results of the sensitivity analyses were comparable. Pre-treatment biomarker levels were similar in patients with and without improvement in pain scores following bisphosphonate therapy. Pre-treatment RANKL and sclerostin were comparable between patients with and without improvement in pain scores after denosumab therapy. Pre-treatment IL-6 level and the RANKL/OPG ratio seemed to be higher in patients with response to denosumab (IL-6: median 0.64 (Q1-Q3 0.53–0.74) pg/mL, n = 6, RANKL/OPG: median 0.062 (Q1-Q3 0.016–0.331), n = 5) compared to patients without response (IL-6: median 0.35 (0.20–0.54) pg/mL, n = 5, RANKL/OPG: 0.027 (0.024–0.046), n = 4). Pre-treatment IL-6 correlated with the improvement in maximum pain scores (rho 0.962, p < 0.001, n = 9) and average pain scores (rho 0.895, p = 0.001, n = 9) reported during denosumab therapy.
Increased concentrations of RANKL, IL-6, sclerostin and of the RANKL/OPG ratio do not indicate severity of FD/MAS, as no correlation was observed of these potential biomarkers with the classic BTMs and SBS. Biomarker levels did not correlate with pain and had no value in predicting bisphosphonate treatment response. These biomarkers are not superior over the currently used methods of assessing ALP, P1NP and CTX or evaluating SBS to establish disease extent or activity and provide no reliable results. Yet, possibly pre-treatment IL-6 and the RANKL/OPG ratio may have some predictive value for clinical response to denosumab. Therefore, studies investigating disease activity and treatment response should include lesional imaging and patient-reported outcome measures.
•No reliable disease biomarkers exist in fibrous dysplasia/McCune-Albright syndrome.•Studied markers RANKL, OPG, sclerostin, IL6 did not correlate with disease severity.•Neither of these markers correlated with pain or predicted treatment response.•Additional investigations for disease follow-up may include lesional imaging.•This needs to be explored to monitor disease activity and therapy response.
Summary
Bone material properties were assessed using impact microindentation in patients with high-energy trauma fractures. Compared to patients with low-energy trauma fractures, bone material ...strength index was significantly higher in patients with high-energy trauma fractures, and did not differ between patients with osteopenia and those with osteoporosis within each trauma group.
Introduction
Impact microindentation (IMI) is a technique to assess tissue-level properties of bone at the tibia. Bone material strength index (BMSi), measured by IMI, is decreased in patients with low-energy trauma fractures, independently of areal bone mineral density (aBMD), but there is no information about BMSi in patients with high-energy trauma fractures. In the present study, we evaluated tissue-level properties of bone with IMI in patients with high-energy trauma fractures.
Methods
BMSi was measured 3.0 months (IQR 2.0–5.8) after the fracture in 40 patients with high-energy trauma and 40 age- and gender-matched controls with low-energy trauma fractures using the OsteoProbe® device.
Results
Mean age of high- and low-energy trauma patients was 57.7 ± 9.1 and 57.2 ± 7.7 years, respectively (
p
= 0.78). Fracture types were comparable in high- vs low-energy trauma patients. Lumbar spine (LS)-aBMD, but not femoral neck (FN)-aBMD, was higher in high- than in low-energy trauma patients (LS 0.96 ± 0.13 vs 0.89 ± 0.13 g/cm
2
,
p
= 0.02; FN 0.75 ± 0.09 vs 0.72 ± 0.09 g/cm
2
,
p
= 0.09). BMSi was significantly higher in high- than in low-energy trauma patients (84.4 ± 5.0 vs 78.0 ± 4.6,
p
= 0.001), also after adjusting for aBMD (
p
= 0.003). In addition, BMSi did not differ between patients with osteopenia and those with osteoporosis within each trauma group.
Conclusion
Our data demonstrate that BMSi and LS-aBMD, but not FN-aBMD, are significantly higher in high-energy trauma patients compared to matched controls with similar fractures from low-energy trauma. Further studies of non-osteoporotic patients with high-energy trauma fracture with measurements of BMSi are warranted to determine whether IMI might help in identifying those with reduced bone strength.
Background:
In active acromegaly, pathologically elevated GH and IGF-1 levels are associated with increased bone turnover and a high bone mass, the latter being sustained after normalization of GH ...values. In a cross-sectional study design, we have previously reported a high prevalence of vertebral fractures (VFs) of about 60% in patients with controlled acromegaly, despite normal mean bone mineral density (BMD) values. Whether these fractures occur during the active acromegaly phase or after remission is achieved is not known.
Objective:
Our objective was to study the natural progression of VFs and contributing risk factors in patients with controlled acromegaly over a 2.5-year follow-up period.
Methods:
Forty-nine patients (mean age 61.3 ± 11.1 years, 37% female) with controlled acromegaly for ≥2 years after surgery, irradiation, and/or medical therapy and not using bisphosphonates were included in the study. Conventional spine radiographs including vertebrae Th4–L4 were assessed for VFs according to the Genant method. VF progression was defined as development of new/incident fractures and/or a minimum 1-point increase in the Genant scoring of preexisting VFs. BMD was assessed by dual-energy x-ray absorptiometry (Hologic 4500).
Results:
Prevalence of baseline VFs was 63%, being highest in men, and fractures were unrelated to baseline BMD. VF progression was documented in 20% of patients, especially in men and in case of ≥2 VFs at baseline. VF progression was not related to BMD values or BMD changes over time.
Conclusion:
Findings from this longitudinal study show that VFs progress in the long term in 20% of patients with biochemically controlled acromegaly in the absence of osteoporosis or osteopenia. These data suggest that an abnormal bone quality persists in these patients after remission, possibly related to pretreatment long-term exposure to high circulating levels of GH.
In fibrous dysplasia/McCune-Albright syndrome (FD/MAS), mosaic mutations in the GNAS gene lead to locally abnormal bone turnover. Additionally, patients with FD/MAS, particularly with thoracic ...lesions, have an increased risk for breast cancer. Development and progression of breast cancer has been associated with expression of Receptor Activator of NF-κB ligand (RANKL) in mammary tissue, and due to the GNAS mutation, RANKL is systemically increased in patients with FD/MAS. Yet it is unknown whether breast cancer in FD/MAS is also dependent on RANKL. We hypothesized that the GNAS mutation might induce RANKL overproduction and an oncogenic niche in mammary tissue, and examined RANKL expression in breast cancer tissue of patients with FD/MAS compared to controls.
Nine patients with FD/MAS and breast cancer were included and clinical data were retrieved. Patients were matched to controls with breast cancer without FD/MAS based on age and tumor type. Three pregnant breast cancer patients were included as positive controls. Immunohistochemical detection of RANKL was performed on formalin-fixed paraffin-embedded breast cancer specimens. Staining intensity was classified as weak, moderate or intense. The area of positive RANKL staining divided by the total ductal-lobular area was assessed (positive area percentage, PAP). Number of patients with RANKL expression was compared between FD/MAS and control group by chi-square (χ2) test, the PAP by Mann-Whitney U test (MWU).
RANKL expression was observed in 3 patients with FD/MAS (38 %), mainly in healthy tissue, and none of the control patients (χ2p = 0.055). The FD/MAS group demonstrated considerably more intense staining than the control group, comparable to positive controls. The median PAP was 0.64 % (range 0.14–2.04 %) in the 3 FD/MAS patients with RANKL expression, 0.01 % (Q1-Q3: 0.0003–0.514 %) in the entire FD/MAS group, 0.006 % (Q1-Q3: 0.001–0.012 %) in the control group (MWU = 0.574), and 0.19 % (0.08–0.32 %) in the pregnant patients. All patients with FD/MAS and RANKL expression had thoracic bone lesions, but no correlation was observed between RANKL expression and presence of the GNAS mutation or FD disease burden.
The triad of a higher number of patients, higher positive area percentage and stronger intensity in the FD/MAS compared to the control group indicates that RANKL may be upregulated in mammary tissue in a subset of patients with FD/MAS, which may explain the increased risk for breast cancer, although the clinical significance remains unclear. Further research is needed to establish risk profiles for the development of RANKL-positive breast cancer and to improve early screening and treatment.
•Patients with fibrous dysplasia/McCune-Albright syndrome may develop breast cancer.•A subset of patients expressed RANKL in breast tissue, mainly in healthy tissue.•Control subjects with breast cancer without the disease expressed no RANKL.•RANKL expression is also known to be elevated in diseased bone in fibrous dysplasia.•RANKL possibly links the bone abnormalities with the increased breast cancer risk.
Fibrous dysplasia (FD) is a genetic, noninheritable rare bone disease caused by a postzygotic activating mutation of the α subunit of the stimulatory G‐protein causing increased abnormal bone ...formation leading to pain, deformity and fractures. To date, no cure has been identified for FD/McCune–Albright syndrome (MAS) and treatment is symptomatic and aimed at decreasing pain and/or local bone turnover. Various drugs have been used to achieve clinical improvement in FD/MAS patients including bisphosphonates and denosumab, however further translational studies are also warranted to address unresolved pathophysiological issues and explore novel pharmacological targets for the management of FD/MAS.
In this article, we review literature on the medical treatment of FD/MAS, discuss the unresolved pathophysiological issues and explore novel pharmacological targets for the management of FD/MAS.
Treating chronic diffuse sclerosing osteomyelitis (DSO) is challenging and many treatments have been reported. However, we know of no standard protocol or guidelines. In this systematic review of ...relevant publications we provide an overview of the different treatments used. We made an electronic search of PubMed, Medline, Embase, Web of Science, and the Cochrane Library databases, for papers that described the treatment of DSO of the mandible. The search yielded 48 papers that applied to all inclusion criteria, resulting in 16 case reports, 13 case series, 18 retrospective clinical cohort studies, and one randomised controlled trial. Reported treatment options included different operations; the use of antibiotics, anti-inflammatories, and antiresorptive medication; conservative treatment; and hyperbaric oxygen. Surgical treatment resulted in a low success rate and was associated with higher morbidity than other treatments. Conservative treatment, and that of bisphosphonates, yielded more promising results, so conservative treatment and bisphosphonates seem to be the most promising therapeutic options. However, because of the high risk of bias, no firm conclusions can be drawn, and larger studies with clear inclusion criteria and specified endpoints are needed.
Summary
We evaluated the relationship between bone material strength index (BMSi) and fragility fractures, including vertebral fractures. Our data showed that BMSi is low in all fracture patients ...with low bone mass, independently of whether patients sustained a vertebral or a non-vertebral fracture.
Introduction
Impact microindentation (IMI) is a new technique for the measurement of tissue level properties of cortical bone in vivo. Previous studies showed an association between BMSi and non-vertebral fractures, but an association with vertebral fractures is still being debated. The objective of this paper was to evaluate the relationship between BMSi and different types of fragility fractures, including vertebral fractures.
Methods
In this cross-sectional study, we measured BMSi in patients of both sexes with different types of fragility fractures and low bone mass with the IMI method using the Osteoprobe®. Vertebral fractures were diagnosed and graded on lateral spine radiographs.
Results
A total of 132 patients were included in the study, of whom 101 patients (65 women) had sustained a low energy fracture and 31 (mean age 57.7 ± 9.9 years) had no history or radiological evidence for a fracture. Of the fracture patients, 53 (mean age 62.8 ± 8.3 years) had only non-vertebral fractures (VF−/Fx+), 34 (mean age 62.8 ± 9.9 years) had vertebral and non-vertebral fractures (VF+/Fx+), and 14 (mean age 64.7 ± 9.3 years) had only vertebral fractures (VF+/Fx−). BMSi values, adjusted for age and BMD, were similar for all three groups of fracture patients (78.9 ± 0.7, 78.3 ± 0.9, and 78.4 ± 1.4, respectively;
p
= 0.866). BMSi values were not associated with number or severity of vertebral fractures.
Conclusion
Our data demonstrate that BMSi is low in fracture patients with low bone mass, irrespective of whether they sustained a vertebral fracture or a non-vertebral fracture.
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