Italian position paper (SIPMO-SICMF) on medication-related osteonecrosis of the jaw (MRONJ).

OBJECTIVE: This paper aims to describe the 2023 update position paper on MRONJ developed by the Italian Societies of Oral Pathology and Medicine (SIPMO) and of Maxillofacial Surgery (SICMF). METHODS: This is the second update following the 2013 and 2020 Italian position papers by the Expert panel, which is a representation of the two scientific societies (SIPMO and SICMF). The paper is based on an extensive analysis of the available literature from January 2003 to February 2020, and the subsequent review of literature conducted between March 2020 and December 2022 to include all new relevant published papers to confirm or modify the previous set of recommendations. RESULTS: This position paper highlights the main issues of MRONJ on risk estimates, disease definition, diagnostic pathway, individual risk assessment, and the fundamental role of imaging in the diagnosis, classification, and management of MRONJ. CONCLUSION: The Expert Panel confirmed the MRONJ definition, the diagnostic work-up, the clinical-radiological staging system and the prophylactic drug holiday, as recognized by SIPMO-SICMF; while, it presented novel indications regarding the categories at risk of MRONJ, the prevention strategies, and the treatment strategies associated with the therapeutic drug holiday.

Effects of a 4400 km ultra-cycling non-competitive race and related training on body composition and circulating progenitors differentiation.

BACKGROUND: NorthCape4000 (NC4000) is the most participated ultra-endurance cycling race. Eight healthy male Caucasian amateur cyclists were evaluated: (a) before starting the preparation period; (b) in the week preceding NC4000 (after the training period); (c) after NC4000 race, with the aim to identify the effects of ultra-cycling on body composition, aerobic capacity and biochemical parameters as well as on the differentiation of progenitor cells. METHODS: Bioelectrical impedance analysis (BIA) and dual energy x-ray absorptiometry (DEXA) assessed body composition; cardiopulmonary exercise test (CPET) evaluated aerobic capacity. Differentiation of circulating progenitor cells was evaluated by analyzing the modulation in the expression of relevant transcription factors. In addition, in vitro experiments were performed to investigate the effects of sera of NC4000 participants on adipogenesis and myogenesis. The effects of NC4000 sera on Sestrins and Sirtuin modulation and the promotion of brown adipogenesis in progenitor cells was investigated as well. Two-tailed Student's paired-test was used to perform statistical analyses. RESULTS: We observed fat mass decrease after training as well as after NC4000 performance; we also recorded that vitamin D and lipid profiles were affected by ultra-cycling. In addition, our findings demonstrated that post-NC4000 participant's pooled sera exerted a positive effect in stimulating myogenesis and in inducing brown adipogenesis in progenitor cells. CONCLUSIONS: The training program and Ultra-cycling lead to beneficial effects on body composition and biochemical lipid parameters, as well as changes in differentiation of progenitor cells, with significant increases in brown adipogenesis and in MYOD levels.

The preventive care of medication-related osteonecrosis of the jaw (MRONJ): a position paper by Italian experts for dental hygienists.

PURPOSE: The prevention and early diagnosis of medication-related osteonecrosis of the jaw (MRONJ) is fundamental to reducing the incidence and progression of MRONJ. Many in the field believe that dental hygienists should play an integral role in primary and secondary MRONJ prevention. However, to date, very few publications in the literature have proposed standardised MRONJ protocols, which are dedicated to dental hygienists. The aim of this study was to provide guidance to the health care providers managing MRONJ. METHODS: The expert opinion in this study was developed by dental hygienists from the main Italian technical-scientific associations (Italian Dental Hygienists Association, AIDI and National Union of Dental Hygienists, UNID) and authors of the latest Italian recommendations regarding MRONJ from the field of dentistry and maxillofacial surgery. RESULTS: The oral care protocol outlined in this position paper is focused on the role of dental hygienist in patients at risk or affected by MRONJ, and it regards 3 main issues: primary prevention, secondary prevention and supporting the treatment of MRONJ. Each issue contains easy-to-apply indications and procedures, as described by the authors, regarding the role of the dental hygienist. CONCLUSION: Referring to the main issues under consideration (primary prevention, secondary prevention and the treatment of MRONJ), a clinical examination of periodontal tissue is critical in preventing MRONJ. It is the opinion of the authors of this study that the application of a periodontal screening score is fundamental in defining personalised strategies for patients at risk of MRONJ. By means of these basic procedures, a protocol for assisting the health care provider and the presentation of a practical approach for patients at risk or affected by MRONJ are described in this study.

Management of bone fragility in type 2 diabetes: Perspective from an interdisciplinary expert panel.

AIM: Bone fragility is increasingly recognized as a relevant complication of type 2 diabetes (T2D) and diabetic patients with fragility fractures have higher mortality rates than non diabetic individuals or diabetic patients without fractures. However, current diagnostic approaches for fracture risk stratification, such as bone mineral density measurement or the use of risk assessment algorithms, largely underestimate fracture risk in T2D patients. A multidisciplinary expert panel was established in order to in order to formulate clinical consensus recommendations on bone health assessment and management of fracture risk in patients with T2D. DATA SYNTHESIS: The following key questions were addressed: a) which are the risk factors for bone fragility in T2D?, b) which diagnostic procedures can be currently used to stratify fracture risk in T2D patients?, c) which are the effects of antidiabetic treatments on bone?, and d) how to prevent and treat bone fragility in T2D patients? Based on the available data members of this panel suggest that the stratification of fracture risk in patients with diabetes should firstly rely on the presence of a previous fragility fracture and on the individual risk profile, with the inclusion of T2D-specific risk factors (namely T2D duration above 10 yrs, presence of chronic T2D complications, use of insulin or thiazolidinediones and persistent HbA1c levels above 8% for at least 1 year). Two independent diagnostic approaches were then suggested in the presence or the absence of a prevalent fragility fracture, respectively. CONCLUSIONS: Clinical trials in T2D patients at risk for fragility fractures are needed to determine the efficacy and safety of available antiresorptive and anabolic agents in this specific setting.

Management of Osteoporosis in Men: A Narrative Review.

Male osteoporosis is a still largely underdiagnosed pathological condition. As a consequence, bone fragility in men remains undertreated mainly due to the low screening frequency and to controversies in the bone mineral density (BMD) testing standards. Up to the 40% of overall osteoporotic fractures affect men, in spite of the fact that women have a significant higher prevalence of osteoporosis. In addition, in males, hip fractures are associated with increased morbidity and mortality as compared to women. Importantly, male fractures occur about 10 years later in life than women, and, therefore, due to the advanced age, men may have more comorbidities and, consequently, their mortality is about twice the rate in women. Gender differences, which begin during puberty, lead to wider bones in males as compared with females. In men, follicle-stimulating hormones, testosterone, estrogens, and sex hormone-binding levels, together with genetic factors, interact in determining the peak of bone mass, BMD maintenance, and lifetime decrease. As compared with women, men are more frequently affected by secondary osteoporosis. Therefore, in all osteoporotic men, a complete clinical history should be collected and a careful physical examination should be done, in order to find clues of a possible underlying diseases and, ultimately, to guide laboratory testing. Currently, the pharmacological therapy of male osteoporosis includes aminobisphosphonates, denosumab, and teriparatide. Hypogonadal patients may be treated with testosterone replacement therapy. Given that the fractures related to mortality are higher in men than in women, treating male subjects with osteoporosis is of the utmost importance in clinical practice, as it may impact on mortality even more than in women.

Acute Effects of Glucocorticoid Treatment, TNFα or IL-6R Blockade on Bone Turnover Markers and Wnt Inhibitors in Early Rheumatoid Arthritis: A Pilot Study.

Tumor Necrosis Factor (TNF)-α and Interleukin (IL)-6 play a fundamental role in bone loss in rheumatoid arthritis (RA), partly due to the inhibition of the Wnt canonical pathway. The aim of our study was to investigate the short-term effects of three different treatments on Wnt inhibitors (Dkk-1 and sclerostin) and on bone turnover markers (BTMs): N-propeptide of type I collagen (PINP) and C-terminal telopeptide of type I collagen (ß-CTX-I). We performed a retrospective analysis of prospectively collected data. We enrolled women affected by early RA (< 12 months) with active disease (DAS28 ≥ 2.6) despite a 6-month treatment with methotrexate (10-15 mg/week), who then started certolizumab pegol, tocilizumab, or methyl-prednisolone (8 mg/daily). Patients were divided into three groups according to the treatment. Blood samples were collected at baseline, week 1, and week 4. We selected 14 patients treated with certolizumab pegol, 14 patients with tocilizumab, and 20 patients with methyl-prednisolone. No difference between any of the tested parameters was found at baseline. ß-CTX-I, Dkk-1, and sclerostin decreased after 1 week of treatment with certolizumab pegol (- 27% ± 21.5, - 50% ± 13.2, and - 30% ± 30.4, respectively, p < 0.05). Methyl-prednisolone induced similar changes, albeit less marked, on ß-CTX-I and Wnt inhibitors, with a decrease in PINP (- 16.1% ± 16.5, p < 0.05). Tocilizumab did not significantly affect BTMs or Wnt inhibitors. No significant changes were found for PTH and 25OHD. In the first four weeks of treatment, TNFα inhibition showed strong effects on BTMs and Wnt inhibitors, differently from IL-6 blockade. Glucocorticoids induced similar changes; nonetheless, they showed undesired effects on bone formation.

Vitamin D levels strongly influence bone mineral density and bone turnover markers during weight gain in female patients with anorexia nervosa.

OBJECTIVE: The aim of the study was to investigate a potential role for vitamin D status on bone mineral density (BMD) during weight gain in patients with anorexia nervosa (AN). METHOD: Spine and hip BMD assessed by dual-energy X-ray absorptiometry (DXA), serum vitamin D (25-OH-D), N-propeptide of type I collagen (P1NP), C-terminal telopeptide of type I collagen (CTX), and intact parathyroid hormone (PTH) were measured before and after a 20-week intensive weight-restoration program in ninety-one female patients with AN and secondary amenorrhoea. RESULTS: Ninety-one consecutive female patients (age 13-45 years; weight 39.4 ± 5.6 kg, body mass index [BMI] 15.1 ± 1.6 kg m-2 ) were included in the study. Although weight and BMI significantly increased in all patients during treatment, mean BMD only significantly increased at the spine (1.0% ± 3.6%, p = .009). The increase in spine BMD was significantly higher only above post-treatment 25-OH-D levels of 30 ng mL-1 (2.5% vs. 0.5%, respectively, for 25-OH-D ≥ and < 30 ng mL-1 , p = .026). There was a significant decrease in bone resorption (CTX; p = .043) and increased bone formation (P1NP; p < .001) after weight restoration. Nevertheless, a significant increase in PTH was also found, which was inversely correlated with decreased post-treatment 25-OH-D levels (R2 = .153, p < .001). DISCUSSION: Hypovitaminosis D may counteract the efficacy of refeeding in AN through increased bone resorption mediated by secondary hyperparathyroidism, which strongly supports the use of vitamin D supplements for bone health in AN.

Prescription of anti-osteoporosis medications after hospitalization for hip fracture: a multicentre Italian survey.

PURPOSE: Literature data indicate that the proportion of patients with recent hip fracture who receive a prescription for anti-osteoporotic drugs is low and does not seem to increase over time. This study aimed to obtain data on the prescription for anti-osteoporotic drugs in Italian patients discharged after a recent hip fracture and to assess which variables could have influenced the decision for prescribing osteoporosis medication. METHODS: A total of four Italian centres located in four different geographical areas (Siena, Verona, Naples and Palermo) participated in this retrospective study. In each centre, experienced clinicians gathered the data of up to 200 consecutive patients discharged after a recent low-trauma hip fracture. The analysis was carried out on 697 patients (540 women and 157 men; mean age 81.9 ± 8.6 years). RESULTS: The percentage of patients who were receiving any type of treatment for osteoporosis before the hip fracture was 8.8% (ranging from 2.4% in Naples to 17.4% in Verona). After the index hip fracture, only 23.2% of patients (namely 10.5% of men and 27.2% of women) received prescription for any pharmacological treatments for osteoporosis. Both female gender and previous use of medications for osteoporosis were positively associated with the likelihood of receiving prescription for anti-osteoporotic treatment at discharge. CONCLUSIONS: This study showed that less than 25% of the elderly Italian patients discharged after a hip fracture received a prescription for any type of treatment for osteoporosis and highlights the urgent need for implementing new strategies in the management of hip fracture patients.

Diagnostic imaging to detect and evaluate response to therapy in bone metastases from prostate cancer: current modalities and new horizons.

Different therapeutic options for the management of prostate cancer (PC) have been developed, and some are successful in providing crucial improvement in both survival and quality of life, especially in patients with metastatic castration-resistant PC. In this scenario, diverse combinations of radiopharmaceuticals (for targeting bone, cancer cells and receptors) and nuclear medicine modalities (e.g. bone scan, SPECT, SPECT/CT, PET and PET/CT) are now available for imaging bone metastases. Some radiopharmaceuticals are approved, currently available and used in the routine clinical setting, while others are not registered and are still under evaluation, and should therefore be considered experimental. On the other hand, radiologists have other tools, in addition to CT, that can better visualize bone localization and medullary involvement, such as multimodal MRI. In this review, the authors provide an overview of current management of advanced PC and discuss the choice of diagnostic modality for the detection of metastatic skeletal lesions in different phases of the disease. In addition to detection of bone metastases, the evaluation of response to therapy is another critical issue, since it remains one of the most important open questions that a multidisciplinary team faces when optimizing the management of PC. The authors emphasize the role of nuclear modalities that can presently be used in clinical practice, and also look at future perspectives based on relevant clinical data with novel radiopharmaceuticals.

Targeting bone metastatic cancer: Role of the mTOR pathway.

One of the great challenges of cancer medicine is to develop effective treatments for bone metastatic cancer. Most patients with advanced solid tumors will develop bone metastasis and will suffer from skeletal related events associated with this disease. Although some therapies are available to manage symptoms derived from bone metastases, an effective treatment has not been developed yet. The mammalian target of rapamycin (mTOR) pathway regulates cell growth and survival. Alterations in mTOR signaling have been associated with pathological malignancies, including bone metastatic cancer. Inhibition of mTOR signaling might therefore be a promising alternative for bone metastatic cancer management. This review summarizes the current knowledge on mTOR pathway signaling in bone tissue and provides an overview on the known effects of mTOR inhibition in bone cancer, both in in vitro and in vivo models.

Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial.

BACKGROUND: Zoledronic acid reduces skeletal-related events in patients with breast cancer, but concerns have been raised about prolonged monthly administration. We assessed the efficacy and safety of a reduced dosing frequency of zoledronic acid in women treated previously with monthly zoledronic acid. METHODS: We did this non-inferiority, phase 3 trial in 62 centres in Italy. We enrolled patients with breast cancer who had one or more bone metastases and had completed 12-15 months of monthly treatment with zoledronic acid. Patients were randomly assigned with a permutated block (size four to eight) random list stratified by centre in a 1:1 ratio to zoledronic acid 4 mg once every 12 weeks or once every 4 weeks, and followed up for at least 1 year. Neither patients nor investigators were masked to treatment allocation. The primary outcome was skeletal morbidity rate (skeletal-related events per patient per year) in the intention-to-treat population. We used a non-inferiority margin of 0.19. The trial is registered with EudraCT, number 2005-004942-15. FINDINGS: We screened 430 patients and enrolled 425, of whom 209 were assigned to the 12-week group and 216 to the 4-week group. The skeletal morbidity rate was 0.26 (95% CI 0.15-0.37) in the 12-week group versus 0.22 (0.14-0.29) in the 4-week group. The between-group difference was 0.04 and the upper limit of one-tailed 97.5% CI was 0.17, which is lower than the non-inferiority margin. The most common grade 3-4 adverse events were bone pain (56 [27%] patients in the 12-week group vs 65 [30%] in the 4-week group), nausea (24 [11%] vs 33 [15%]), and asthenia (18 [9%] vs 33 [15%]). Renal adverse events occurred in one patient (<1%) in the 12-week group versus two (1%) in the 4-week group. One patient (<1%) in the 4-week group had grade 1 acute renal failure. Osteonecrosis of the jaw occurred in four patients in the 12-week group versus three in the 4-week group. No treatment-related deaths were reported. Median N-terminal telopeptide concentration changed from baseline more in the 12-week group than in the 4-week group after 12 months (12.2% vs 0.0%; p=0.011). INTERPRETATION: Our results raise the possibility of decreasing administration of zoledronic acid to a 12-weekly regimen to reduce exposure during the second year, while maintaining its therapeutic effects. However, the effects on N-terminal telopeptide should be investigated further before changing current practice. FUNDING: Novartis Farma.

Risk of fracture in women with glucocorticoid requiring diseases is independent from glucocorticoid use: An analysis on a nation-wide database.

OBJECTIVE: Glucocorticoid-induced osteoporosis (GIOP) is a common cause of secondary osteoporosis. However, glucocorticoid requiring diseases pose a risk themselves for fracture. The aim of the present study was to determine the risk of fracture associated with variety of glucocorticoid requiring diseases independently from glucocorticoid use and other risk factors for osteoporosis. METHODS: We conducted a retrospective cross-sectional analysis of a nation-wide cohort (DeFRACalc79 database). We used multivariable regression analysis adjusting for several risk factors for fracture and glucocorticoid intake to estimate the independent role of glucocorticoid requiring illnesses on fracture risk. RESULTS: We found that patients with rheumatoid arthritis, connective tissue diseases, chronic obstructive pulmonary disease (COPD) and neurological diseases were at greater risk of vertebral or hip fracture (crude ORs 1.31, 1.20, 1.92 and 2.97 respectively). After adjusting for potential confounders COPD and neurological diseases remained significantly associated with an increased risk of vertebral or hip fractures (aORs 1.33, 95 % CI 1.18-1.49 and 2.43, 95 % CI 2.17-2.74). Rheumatoid arthritis, COPD, IBD and neurological diseases also significantly increased the risk of non-vertebral, non-hip fractures (aORs 1.23, 1.42, 1.52 and 1.94 respectively). CONCLUSION: Some glucocorticoid requiring diseases were independently associated with an increased risk of fractures. COPD and neurological diseases with both vertebral and non-vertebral fracture risk while RA and IBD were independently associated only with non-vertebral, non-hip fractures.

Possible role of bone turnover markers in the diagnosis of adult hypophosphatasia.

Hypophosphatasia (HPP) is a rare disorder of the bone metabolism, characterized by genetically-determined low alkaline phosphatase (ALP) activity. Low ALP may also be observed in some common causes of bone fragility, such as in osteoporosis treated with antiresorptive drugs. This study aimed to verify whether differences in bone turnover markers (BTMs) could help differentiate adult patients with HPP from those with osteoporosis undergoing antiresorptive treatment. In this multicenter study, we enrolled 23 adult patients with a diagnosis of HPP and compared them with 46 osteoporotic subjects previously treated with zoledronic acid or denosumab. BTMs such as C-terminal telopeptide of type I collagen (CTX), N-terminal propeptide of type I procollagen (P1NP), total ALP, and bone ALP (bALP) were measured, and ratios between BTMs were also calculated. Considering that the control group included only females, in the primary analysis we compared their characteristics with that of the 16 female patients with HPP. Both individual BTMs (CTX and P1NP) and four BTM ratios (ALP/P1NP, bALP/P1NP, ALP/CTX, and bALP/CTX) showed satisfactory discriminatory power, outperforming ALP alone. P1NP, in particular, had an AUC of 0.962 with a cut-off of 32 µg/L, while as for the BTMs ratios, the ALP/P1NP ratio had an AUC of 0.964 with a cut-off of 1.114. Similar results were confirmed when including male HPP patients, when adjusting for age and sex, and finally when performing a sensitivity analysis only in patients with ALP less than or equal to 32 U/L (i.e., the median of the distribution of the entire population). In cases of low ALP and bone fragility, BTM and their ratios could help distinguish HPP patients from osteoporotic individuals treated with antiresorptive drugs, aiding in accurate diagnosis and reducing the risk of inappropriate treatment.

Hypophosphatasia (HPP) is a rare bone disease caused by mutations in the ALPL gene, leading to low activity of alkaline phosphatase (ALP). This enzyme deficiency affects bone mineralization, causing a wide range of symptoms, with severe cases potentially resulting in stillbirth. In contrast, milder forms can be mistaken for common bone diseases like antiresorptive-treated osteoporosis, leading to misdiagnosis and inappropriate treatments that may worsen bone fragility in HPP patients. Diagnosing HPP primarily relies on measuring plasma ALP activity, but low ALP is not specific to HPP and can occur in other conditions. Confirmatory tests, including specific biomarkers and genetic analysis, are often expensive and not widely available. Our study explores the use of bone turnover markers (BTMs) to help diagnose HPP. We found that HPP patients show distinct patterns in BTMs compared to those with antiresorptive-treated osteoporosis. These findings suggest that measuring BTMs and their ratios could help distinguish HPP from primary osteoporosis in patients with low ALP and bone fragility. This approach could lead to earlier and more accurate diagnoses, prompting further specific tests for HPP. More research is needed to confirm these findings in other conditions with low ALP activity.

Treatment thresholds for osteoporosis and reimbursability criteria: perspectives associated with fracture risk-assessment tools.

The definition of osteoporosis was based for several years on bone mineral density values, which were used by most guidelines for defining treatment thresholds. The availability of tools for the estimation of fracture risk, such as FRAX™ or its adapted Italian version, DeFRA, is providing a way to grade osteoporosis severity. By applying these new tools, the criteria identified in Italy for treatment reimbursability (e.g., "Nota 79") are confirmed as extremely conservative. The new fracture risk-assessment tools provide continuous risk values that can be used by health authorities (or "payers") for identifying treatment thresholds. FRAX estimates the risk for "major osteoporotic fractures," which are not counted in registered fracture trials. Here, we elaborate an algorithm to convert vertebral and nonvertebral fractures to the "major fractures" of FRAX, and this allows a cost-effectiveness assessment for each drug.

Bone Mineral Density in Mountain, Road Cyclists and Untrained Controls: Exercise, Diet and Hormones.

Purpose: The aim of the study was to compare bone mineral density (BMD) in the lumbar spine (LSBMD) and the femoral neck (FBMD) in male road cyclists (RC n = 39), mountain cyclists (MC n = 30) and controls (C n = 27) and to determine the factors associated with BMD in the same group of participants. Methods: BMD, fat mass (FM) and fat-free mass (FFM) were measured using DXA. Calcium intake (Cal), exercise energy expenditure (EEE) and energy availability (EA) were assessed using self-reported questionnaires. Samples for circulating hormones were also obtained. VO2max was estimated by a cycloergometric test. Results: After adjustment for body mass, in cyclists LSBMD (RC 0.98 ± 0.12; MC 0.98 ± 0.10 g/cm2) was significantly lower than in C (1.11 ± 0.10; p < .001), while FBMD resulted in no significant difference in cyclists compared to C (p = 0.213). EA (kcal/FFM/day) was different in cyclists and in C (p < .05). In C, EEE and EA were positively associated with LSBMD (R = 0.561, R = 0.656, respectively, p < .01), whereas only EA was associated with FBMD (R = 0.554, p < .05); a positive association between EA and FBMD was found in MC (R = 0.464, p < .05). A negative relationship between VO2max and LSBMD in RC (R = -0.418, p < .05) and a positive one between EEE and LSBMD in MC were found (R = 0.605, p < .001). CaI, free testosterone and cortisol were unrelated to BMD. Conclusion: Both the RC and MC had lower LSBMD than C, whereas no difference was found between the two groups of cyclists. The factors associated with BMD are manifold, vary in relation to the measurement site and are likely different in RC, MC and C.

Reply to Wimalawansa, S.J. Comment on "Bertoldo et al. Definition, Assessment, and Management of Vitamin D Inadequacy: Suggestions, Recommendations, and Warnings from the Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS). Nutrients 2022, 14, 4148".

With regard to Dr. Wimalawansa's comment [...].

Osteomalacia: the missing link in the pathogenesis of bisphosphonate-related osteonecrosis of the jaws?

BACKGROUND: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-documented adverse event from treatment with nitrogen-containing bisphosphonates (NBPs). During a preliminary histomorphometric study aimed at assessing the rate of bone remodeling in the jaws of patients with surgically resected BRONJ, we found a defect of bone mineralization (unpublished data). We hypothesized that osteomalacia could be a risk factor for BRONJ in patients taking NBPs. Therefore, we looked for static and dynamic histomorphometric evidence of osteomalacia in biopsies from subjects with and without BRONJ. METHODS: This case-control study used histomorphometric analysis of bone specimens of patients using NBPs (22 patients with BRONJ and 21 patients without BRONJ) who required oral surgical interventions for the treatment/prevention of osteonecrosis. Patients were given tetracycline hydrochloride according to a standardized protocol before taking bone biopsies from their jaws. Biopsies with evidence of osteomyelitis or necrosis at histology were excluded from the study. Osteomalacia was defined as a mineralization lag time >100 days, a corrected mean osteoid thickness >12.5 mm, and an osteoid volume >10%. RESULTS: In all, 77% of patients with BRONJ were osteomalacic compared with 5% of patients without BRONJ, according to histomorphometry. Because osteomalacia was found almost exclusively in NBP users with BRONJ, this is likely to be a generalized process in which the use of NBPs further deteriorates mechanisms of bone repair. CONCLUSIONS: Osteomalacia represents a new and previously unreported risk factor for disease development. This finding may contribute to a better understanding of the pathogenesis of this disease and help with the development of strategies to increase the safety of NBP administration.

The role of bone microenvironment, vitamin D and calcium.

Starting first from Paget's "seed and soil" to the latest hypothesis about metastatic process involving the concept of a premetastatic niche, a large amount of data suggested the idea that metastatization is a multistep coordinated process with a high degree of efficiency. A specific subpopulation of cells with tumor-initiating and migratory capacity can selectively migrate toward sites that are able to promote survival, and/or proliferation of metastatic tumor cells through a microenvironment modification. Bone plays a pivotal role in this process, acting not only as a preferential site for cancer cells' homing and proliferation, due to a complex interplay between different cellular phenotypes such as osteoblasts and osteoclasts, but also as a source of bone marrow precursors that are able to facilitate the metastatic process in extra-skeletal disease. Moreover, bone microenvironment has the unique capacity to retain cancer stem cells in a quiescent status, acting as a reservoir that is able to cause a metastatic spread also many years after the resection of the primary tumor. To add a further level of complexity, these mechanisms are strictly regulated through the signalling through several soluble factors including PTH, vitamin D or calcium concentration. Understanding this complexity represents a major challenge in anti-cancer research and a mandatory step towards the development of new drugs potentially able not only to reduce the consequences of bone lesions but also to target the metastatization process from the "bone pre-neoplastic niche" to "visceral pre-neoplastic niches".