Anti-resorptive therapy and MRONJ. A survey of the Italian Society of Periodontology and Implantology.

OBJECTIVES: Anti-resorptive agents have been linked to the development of MRONJ in patients undergoing dental surgical procedures. This survey aims to explore the level of knowledge and experience of Italian Society of Periodontology and Implantology members in the management of patients treated with anti-resorptive agents and with the risk of developing MRONJ. MATERIALS AND METHODS: An 18-item questionnaire was submitted by e-mail to the SIdP members. Statistical analyses were carried out. Continuous variables were described as mean ± standard deviation (SD) or median, and first and third quartile according to distribution's normality. Normality of data was checked with Shapiro-Wilk test. RESULTS: Four hundred and fifty-one questionnaires were returned by e-mail (32%). Most of the respondents were private practitioners (81.8%). Only 47.7% declared to be highly confident in managing patients on anti-resorptive therapy while 92.5% reported to have performed tooth extractions and 52.3% implant surgery in patients under anti-resorptive therapy for osteometabolic disorders. One or more MRONJ-affected patients were encountered by 63.2% of the respondents. CONCLUSIONS: This survey highlights the need to develop a "dedicated" program both for dentists and prescribers to improve the level of cooperation and to increase the level of awareness of patients treated with anti-resorptive agents.

Anti-resorptive therapy in the osteometabolic patient affected by periodontitis. A joint position paper of the Italian Society of Orthopaedics and Traumatology (SIOT) and the Italian Society of Periodontology and Implantology (SIdP).

This joint report from the Italian Society of Orthopaedics and Traumatology (SIOT) and the Italian Society of Periodontology and Implantology (SIdP) aims for a consensus around the scientific rationale and clinical strategy for the management of osteoporotic patients affected by periodontitis who are undergoing anti-resorptive (AR) therapy to manage the risk of the occurrence of a medication-related osteonecrosis of the jaws (MRONJ). Osteoporosis and periodontitis are chronic diseases with a high prevalence in aging patients, and they share some of the same pathogenetic mechanisms based upon inflammation. Available evidence shows the relationship among osteoporosis, AR agents, periodontitis and implant therapy in relation to the incidence of MRONJ. Uncontrolled periodontitis may lead to tooth loss and to the need to replace teeth with dental implants. Tooth extraction and surgical dental procedures are recognized as the main risk factors for developing MRONJ in individuals taking AR therapy for osteometabolic conditions. Although the incidence of MRONJ in osteometabolic patients taking AR therapy may be as low as 0.9%, the increasing prevalence of osteoporosis and the high prevalence of periodontitis suggest that this potential complication should not be overlooked. Good clinical practice (GCP) guidelines are proposed that aim at a more integrated approach (prescriber, dentist, periodontist and dental hygienist) in the management of periodontitis patients undergoing AR therapy for osteometabolic disorders to reduce the risk of MRONJ. Dental professional and prescribers should educate patients regarding the potential risk associated with the long-term use of AR therapy and oral health behavior.

Bisphosphonates, Bone and Joint Pain.

PURPOSE OF REVIEW: Bisphosphonates (BPs) have an established role in a number of diseases including osteoporosis, but the role of BPs for treating symptomatic conditions other than bone metastases is less clear. We review recent data on the efficacy of BPs in the treatment of symptomatic bone and joint pain with osteoarthritis (OA) as an example. RECENT FINDINGS: Although controversial, BPs have been reported to improve pain ratings, imaging features, and inflammatory markers in patients with arthritis, more specifically OA. It is possible that their effects in periarticular bone strongly influence the complex inflammatory process within the joints. Recent data also suggests that they can potentially impact synovial and synoviocytes and macrophages. Although more studies are needed to define their contribution in clinical practice, increasing evidence suggests they hold an important function, especially in conditions with periarticular bone involvement such as OA. Although BPs are indicated primarily for prevention and treatment of osteoporosis, they can also have potential effects on the inflammatory process of other conditions, including OA. Improvements in pain scale ratings, periarticular findings through imaging, and inflammatory response suggest their potential extra-osteoporotic properties.

From Osteoclast Differentiation to Osteonecrosis of the Jaw: Molecular and Clinical Insights.

Bone physiology relies on the delicate balance between resorption and formation of its tissue. Bone resorption depends on a process called osteoclastogenesis in which bone-resorbing cells, i.e., osteoclasts, are produced by the differentiation of more undifferentiated progenitors and precursors. This process is governed by two main factors, monocyte colony-stimulating factor (M-CSF) and receptor activator of NFκB ligand (RANKL). While the former exerts a proliferating effect on progenitors/precursors, the latter triggers a differentiation effect on more mature cells of the same lineage. Bone homeostasis requires a perfect space-time coordination of the involved signals. When osteoclastogenesis is poorly balanced with the differentiation of the bone forming counterparts, i.e., osteoblasts, physiological bone remodelling can turn into a pathological state, causing the systematic disruption of bone tissue which results in osteopenia or osteolysis. Examples of these conditions are represented by osteoporosis, Paget's disease, bone metastasis, and multiple myeloma. Therefore, drugs targeting osteoclastogenesis, such as bisphosphonates and an anti-RANKL monoclonal antibody, have been developed and are currently used in the treatment of such diseases. Despite their demonstrated therapeutic efficacy, these agents are unfortunately not devoid of side effects. In this regard, a condition called osteonecrosis of the jaw (ONJ) has been recently correlated with anti-resorptive therapy. In this review we will address the involvement of osteoclasts and osteoclast-related factors in the pathogenesis of ONJ. It is to be hoped that a better understanding of the biological mechanisms underlying bone remodelling will help in the design a medical therapeutic approach for ONJ as an alternative to surgical procedures.

Pitfalls in bone density monitoring in prostate cancer during anti-resorptive treatment.

A 74-year-old man presented to the Andrology Clinic for management of potential complications of androgen deprivation therapy for prostate cancer. He had a rising prostate-specific antigen with a concurrent rise in alkaline phosphatase and bone remodeling markers. This was despite treatment with a radical prostatectomy, androgen deprivation, and anti-resorptive therapy. A follow-up dual-energy X-ray absorptiometry scan revealed a marked increase in his bone mineral density at both the lumbar spine and femoral neck. This increase, especially in the context of rising bone remodeling markers, was unlikely due to the effect of anti-resorptive therapy alone. Subsequent whole-body bone scintigraphy demonstrated a "superscan" phenomenon which is characterized by uniform and avid tracer retention throughout the skeleton, in this case due to widespread skeletal metastasis, so that the usual physiological uptake in the kidneys is no longer observed and can be misinterpreted as a "normal" scan if the absence of the kidneys is not recognized. This case highlights the importance of considering diffuse metastatic disease when there is a rapid increase in bone mineral density, even in individuals treated with anti-resorptive therapy.

Atypical fractures at non-classical sites associated with anti-resorptive therapy: A Systematic Review.

BACKGROUND: Osteoporosis is common, affecting more than 20% of women and 6% of men globally over the age of 50 (1). Anti-resorptive drugs, bisphosphonates and denosumab, have been effective treatments for osteoporosis for more than 30 years. Rare complications of anti-resorptive therapy include medication-related osteonecrosis of the jaw and atypical femur fractures (AFF). The American Society for Bone and Mineral Research (ASBMR) proposed a case definition for these atypical femoral fractures in 2010, which was updated in 2013. However, atypical fractures at non-classical sites have been increasingly described. AIMS: We aimed to systematically identify atypical fracture cases, excluded from the ASBMR AFF case definition in patients receiving anti-resorptive medication for longer than three years. METHODS: A structured search of electronic databases, including PubMed, Medline (Ovid), Embase (Ovid), Cochrane and Web of Sciences, and hand-searching of conference abstracts was undertaken. All full-text articles written in English describing an atypical fracture in patients (aged >18 years) and receiving anti-resorptive medication for >3 years were included, with data extracted and analysed by two independent reviewers. RESULTS: Sixty-six articles were identified, describing 151 cases of atypical fractures in 114 individuals. The most frequent fracture site was the ulna, followed by the tibia. All patients were taking anti-resorptive treatment prior to or at the time of fracture, most frequently alendronate monotherapy (44%). Most commonly, fractures were transverse in nature (95%), following minimal or no trauma (96%), non-comminuted (98%) with cortical thickening of the surrounding bone (69%). Anti-resorptive treatment was ceased following atypical fracture in the majority (89%). CONCLUSIONS: Atypical fractures are rare and should not deter physicians from appropriate anti-resorptive therapy for osteoporosis. However, clinicians should be alert to their presence, at additional sites to the femur. An update of the current ASBMR AFF case definition to include other skeletal sites could be timely.

Bisphosphonates and denosumab, anti-resorptive medications, have been effective treatments for osteoporosis for more than 30 years. Rare but serious side effects of these therapies include medication-related osteonecrosis of the jaw and atypical femur (thigh bone) fractures. Increasingly however, atypical fractures at non-classical sites have been described. To address this, we systemically reviewed published cases of atypical fractures at sites other than the femur. We identified 151 cases of atypical fractures in 114 individuals. The most frequent site was the ulna, followed by the tibia. All patients were taking anti-resorptive medication prior to or at the time of fracture, most frequently alendronate (44%). Most commonly, fractures were transverse in nature (95%), following minimal or no trauma (96%), non-comminuted (98%) with cortical thickening of the surrounding bone (69%). Although rare, clinicians should be alert to the presence of atypical fractures at sites additional to the femur. If confirmed to be an atypical fracture in the setting of anti-resorptive therapy, we recommend considering cessation of anti-resorptive treatment, limit weight-bearing, consider surgical management and manage their underlying osteoporosis.

Associations of estrogen therapy and non-estrogen anti-resorptive therapy with diabetes mellitus risk: A classical and Bayesian meta-analysis.

Anti-resorptive therapy (AT) increases insulin resistance and decrease insulin secretion through reduced undercarboxylated osteocalcin in mice. However, there are inconsistent findings regarding the impact of AT use on the risk of diabetes mellitus in humans. We examined the association between AT and incident diabetes mellitus using classical and Bayesian meta-analysis. We searched Pubmed, Medline, Embase, Web of Science, Cochrane, and Google Scholar for studies listed from database inception to 25 February 2022. Randomized controlled trials (RCTs) and cohort studies reporting associations of estrogen therapy (ET) and non-estrogen anti-resorptive therapy (NEAT) with incident diabetes mellitus were included. Two reviewers independently extracted research data such as ET and NEAT, diabetes mellitus, risk ratios (RRs), and 95 % confidence intervals (CIs) for incident diabetes mellitus associated with ET and NEAT from individual studies. This meta-analysis included data from nineteen original studies, consisting of fourteen ET and five NEAT studies. ET was associated with reduced risk of diabetes mellitus in the classical meta-analysis (RR: 0.90; 95 % CI: 0.81-0.99). Slightly stronger results were found in the meta-analysis of RCTs (RR: 0.83; 95 % CI: 0.77-0.89). The probability that RR < 1.0 was 95 % in the overall analysis and 99 % in RCTs under weakly informative prior. Although NEAT was associated with reduced risk of diabetes mellitus overall (RR: 0.80; 95 % CI: 0.67-0.97), this was not found in the RCT meta-analysis (RR: 0.90; 95 % CI: 0.75-1.10). Under weakly informative prior, the probabilities that NEAT reduces diabetes mellitus by >0 % were 99 %, and 73 % in the overall and RCT meta-analysis, respectively. In conclusion, meta-analysis provided consistent evidence against the hypothesis that AT increases diabetes risk. ET may reduce the risk of diabetes mellitus. Whether NEAT reduces the risk of diabetes mellitus is uncertain and requires additional evidence from RCTs.

Denosumab is effective in the treatment of bone marrow oedema syndrome.

Bone marrow oedema (BMO) syndrome describes a painful condition with increase of interstitial fluid within bone and is often lately diagnosed due to unspecific symptoms. The underlying causes are diverse while it is widely assumed that in cases of BMO local bone resorption is increased. Denosumab, a human monoclonal antibody that binds to the receptor activator of nuclear factor kappa-B ligand (RANKL) inhibits osteoclastic bone resorption and is commonly administered in the treatment of osteoporosis. Besides one previous case report, its clinical effectiveness in the treatment of bone marrow oedema has not been elucidated. We treated 14 patients with primary (idiopathic) bone marrow oedema of the lower extremity with single dose denosumab application. Mean time between onset of pain and therapy was 155days. MRI scans were performed for initial diagnosis, and 6-12 weeks after denosumab injection. Vitamin D and calcium homeostasis were strived to be balanced before initiation of therapy. Furthermore bone status was analysed using Dual-energy X-ray absorptiometry (DXA) and extended bone turnover serum markers. After 6-12 weeks, BMO dissolved partly or completely in 93%, while a complete recovery was observed in 50% of the individuals. Visual analogue scale (VAS) evaluation revealed a significant decrease in pain level. Furthermore, bone turnover decreased significantly after treatment. No adverse reactions were reported. In conclusion, our retrospective analysis shows that denosumab is highly effective in the treatment of bone marrow oedema and therefore represents an alternative treatment option.

Femoral shaft strains during daily activities: Implications for atypical femoral fractures.

BACKGROUND: Atypical femoral fractures are low-energy fractures initiating in the lateral femoral shaft. We hypothesized that atypical femoral fracture onset is associated with daily femoral strain patterns. We examined femoral shaft strains during daily activities. METHODS: We analyzed earlier calculations of femoral strain during walking, sitting and rising from a chair, stair ascent, stair descent, stepping up, and squatting based on anatomically consistent musculoskeletal and finite-element models from a single donor and motion recordings from a body-matched volunteer. Femoral strains in the femoral shaft were extracted for the different activities and compared. The dependency between femoral strains in the lateral shaft and kinetic parameters was studied using multi-parametric linear regression analysis. FINDINGS: Tensile strain in the lateral femoral shaft varied from 327 µÎµ (squatting) to 2004 µÎµ (walking). Walking and stair descent imposed tensile loading on the lateral shaft, whereas the other activities mainly imposed tensile loads on the anterior shaft. The multi-parametric linear regression showed a moderately strong correlation between tensile strains in the lateral shaft and the motion kinetic (joint moments and ground reaction force) in the proximal (R(2)=0.60) and the distal shaft (R(2)=0.46). INTERPRETATION: Bone regions subjected to tensile strains are associated with atypical femoral fractures. Walking is the daily activity that induces the highest tensile strain in the lateral femoral shaft. The kinetics of motion explains 46%-50% of the tensile strain variation in the lateral shaft, whereas the unexplained part is likely to be attributed to the way joint moments are decomposed into muscle forces.