Risk Of Osteonecrosis In Patients Research Articles

Clinical characteristics and risk factors in 118 patients with systemic lupus erythematosus and osteonecrosis

Objective: To investigate the clinical characteristics and risk factors for osteonecrosis (ON) in patients with systemic lupus erythematosus (SLE). Methods: This is a case-control study. A total of 118 patients diagnosed with SLE complicated with ON (study group) were retrospectively analyzed between 2014 and 2019. Gender, age, and course matched 118 SLE patients without ON were selected as controls. Clinical manifestations, laboratory findings, medical history, and treatments were recorded and analyzed. Results: Among 118 patients, the male to female ratio was 20 to 98 with a median age of 27 years and course of disease 1-168 months. Compared with the control group, the study group presented a longer cumulative duration of glucocorticoid therapy [36.5 (0-168) months vs. 19.0(0-168) months on average, P<0.05], a higher incidence of osteoporosis (29.7% vs. 4.2%, P<0.001), a higher frequency of immune-suppressive therapy (83.9% vs. 64.4%, P=0.035), more organs involveed [median 2 (0-5) vs. 1 (0-4)], and a higher SLE disease activity index (SLEDAI) (14.22±7.40 vs. 11.63±6.11, P<0.05) in univariate logistic regression. The control group had a higher rate of positive Coombs test (39.8% vs. 7.6%, P<0.05). No statistical difference on methylprednisolone (MP) pulse therapy (P>0.05) was observed. Multivariate logistic regression suggested that SLEDAI (OR= 1.070, 95%CI 1.026-1.116, P<0.005), osteoporosis (OR=10.668, 95%CI 3.911-29.103, P<0.001) and a positive Coombs test(OR=0.492, 95%CI 0.266-0.910, P<0.05) were related to the development of ON in SLE patients. Conclusion: A higher disease activity and the presence of osteoporosis are associated with an increased risk of ON in patients with SLE, and positive Coombs test seems a protective factor of ON.

Medication-Related Osteonecrosis of the Jaws and CDK4/6 Inhibitors: A Recent Association.

The purpose of the present study was to estimate the prevalence of cyclin-dependent kinase (CDK) 4/6 inhibitors use among cancer patients from the medication-related osteonecrosis of the jaw (MRONJ) cohort of the University of Messina. We retrospectively reviewed the records of all patients with either intravenous bisphosphonates or denosumab-related MRONJ reported in the electronic health records of the Unit of Oral Surgery, School of Dentistry, University of Messina between the first quarter of 2018 and the first quarter 2020 to identify eligible patients. We observed six cases of MRONJ associated with CDK4/6 inhibitors concomitantly with intravenous bisphosphonates and/or denosumab in breast cancer patients. The CDK4/6 inhibitors registered were palbociclib (n = 5) and abemaciclib (n = 1). Data of cancer patients diagnosed with MRONJ in the same period (n = 10) were extracted for comparison. The comparative assessment with this group of patients showed a similar distribution of MRONJ stage ranged and clinical course after treatment. The degree of risk for osteonecrosis in patients taking these new classes of drugs is uncertain but warrants awareness and close monitoring. The role of premedication dental evaluation as a prevention strategy has been acknowledged for cancer patients about to initiate intravenous bisphosphonates and/or denosumab for treatment of bone metastasis, but additional attention should be paid to whom are assuming CDK4/6 inhibitors because of their oral adverse events.

Monitoring of Osteonecrosis in Systemic Lupus Erythematosus: A Systematic Review and Metaanalysis.

Nontraumatic osteonecrosis (ON) is a well-recognized complication causing disability and affecting quality of life in patients with systemic lupus erythematosus (SLE). The aim of this study was to identify the risk factors for ON, and to identify the minimal investigation(s) needed to optimally monitor the risk of ON in patients with SLE. A systematic review was conducted using MEDLINE and EMBASE. These databases were searched up to January 2016 using the Medical Subject Heading (MeSH) terms "Osteonecrosis," "Systemic lupus erythematosus," and synonymous text words. Randomized controlled trials, case control, cohort, and cross-sectional studies were included. Risk factors for ON in patients with SLE were compiled. The quality of each study was assessed using the Newcastle-Ottawa scale for nonrandomized studies. The quality of evidence of each risk factor was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation method. Of the 545 references yielded, 50 met inclusion criteria. Corticosteroid (CS) use may be strongly associated with ON in patients with SLE. Other clinical variables were moderately associated, including hypertension, serositis, renal disease, vasculitis, arthritis, and central nervous system disease. However, the evidence was low to very low in quality. Based on the best evidence available, CS use may be strongly associated with ON in patients with SLE. Results of this review were considered in the development of recommendations for the diagnosis and monitoring of patients with SLE in Canada and will guide clinicians in their assessment of these patients.

Osteonecrosis of the Jaw in the Absence of Antiresorptive or Antiangiogenic Exposure: A Series of 6 Cases

Medication-related osteonecrosis of the jaws (MRONJ) is a well-described complication of antiresorptive and antiangiogenic medications. Although osteonecrosis can be associated with other inciting events and medications, such as trauma, infection, steroids, chemotherapy, and coagulation disorders, these are rarely reported in the literature. This is a six case series of MRONJ associated with medications other than antiresorptive or antiangiogenic drugs. Patient demographics, inciting event, location, stage, imaging findings, and outcome are reported. With the continued development and clinical use of new biologic medications for diseases such as cancer and rheumatoid arthritis, it is important to continue to evaluate their effects on the oral cavity. The degree of risk for osteonecrosis in patients taking these new classes of drugs is uncertain but warrants awareness and monitoring.

Osteonecrosis de los maxilares: fisiopatología, diagnóstico y tratamiento

The human skeleton is an organized set of bony pieces that make up and provide the structural support of the body. Different functions have been described: dynamic and mechanical support, protection and maintenance of mineral homeostasis. For this, the bone must maintain its active metabolism and be able to adapt its structure to mechanical stimuli repairing the structural damages through the process of remodeling throughout the life. Osteoporosis, Paget’s disease, cancer and bone infections, will alter the physiology of the tissue resulting in the loss of its integrity. Bisphosphonates (BFs) are pharmacological agents designed for the treatment of these diseases, their main mechanism of action is the inhibition of bone osteoclastic resorption. Medication related osteonecrosis of the jaw (ONJ) consists of the progressive destruction of the bone tissue, being one of the adverse effects of this type of treatment. For this reason, the objective of this article was to make a review about the main pharmacological and clinical aspects of ONJs related to bisphosphonates in dentistry. Clinical diagnosis and appropriate treatment are essential to reduce the risk of osteonecrosis in patients undergoing antiresorptive therapy or before starting administration. For this reason, prevention is even more important.

Medication-related osteonecrosis of the jaw: Clinical and practical guidelines.

Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse drug reaction, consisting of progressive bone destruction in the maxillofacial region of patients. ONJ can be caused by two pharmacological agents: Antiresorptive (including bisphosphonates (BPs) and receptor activator of nuclear factor kappa-B ligand inhibitors) and antiangiogenic. MRONJ pathophysiology is not completely elucidated. There are several suggested hypothesis that could explain its unique localization to the jaws: Inflammation or infection, microtrauma, altered bone remodeling or over suppression of bone resorption, angiogenesis inhibition, soft tissue BPs toxicity, peculiar biofilm of the oral cavity, terminal vascularization of the mandible, suppression of immunity, or Vitamin D deficiency. Dental screening and adequate treatment are fundamental to reduce the risk of osteonecrosis in patients under antiresorptive or antiangiogenic therapy, or before initiating the administration. The treatment of MRONJ is generally difficult and the optimal therapy strategy is still to be established. For this reason, prevention is even more important. It is suggested that a multidisciplinary team approach including a dentist, an oncologist, and a maxillofacial surgeon to evaluate and decide the best therapy for the patient. The choice between a conservative treatment and surgery is not easy, and it should be made on a case by case basis. However, the initial approach should be as conservative as possible. The most important goals of treatment for patients with established MRONJ are primarily the control of infection, bone necrosis progression, and pain. The aim of this paper is to represent the current knowledge about MRONJ, its preventive measures and management strategies.

Is Age or Surgical Approach Associated With Osteonecrosis in Patients With Developmental Dysplasia of the Hip? A Meta-analysis.

Osteonecrosis of the femoral head is a major complication that negatively impacts the clinical and radiographic long-term outcome after treatment of developmental hip dysplasia (DDH). There are conflicting results in the literature whether age at the time of closed or open reduction and a specific surgical approach are associated with osteonecrosis. Better understanding of the impact of age at reduction and surgical approach is important to reduce the risk of osteonecrosis in patients with DDH. We aimed to evaluate the association between occurrence of osteonecrosis and (1) age at closed reduction; (2) age at open reduction; and (3) medial versus anterior operative approaches. A systematic review identified studies reporting osteonecrosis occurrence after treatment of DDH and at least 2 years of followup. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Methodologic quality was assessed using the methodologic index for nonrandomized studies. Generalized logistic models were used to estimate pooled odds ratios (ORs) in the meta-analysis. Sixty-six studies were included in the systematic review and 24 in the meta-analysis. Data on 481 hips treated by closed reduction and 584 hips treated by open reduction were available to evaluate the association between osteonecrosis and age. The association between osteonecrosis and operative approach was assessed using data on 364 hips treated by medial open reduction and 220 hips treated by anterior open reduction. Age at reduction (> 12 months versus ≤ 12 months) was not associated with osteonecrosis after closed reduction (OR, 1.1; 95% confidence interval [CI], 0.4-3.2; p = 0.9) or open reduction (OR, 1.1; 95% CI, 0.7-1.9; p = 0.66). The overall, adjusted incidence of osteonecrosis (≥ Grade II) was 8.0% (95% CI, 2.8%-20.6%) among patients treated with closed reduction at or before 12 months of age and 8.4% (95% CI, 3.0%-21.5%) among those treated after 12 months. Similarly, the odds of osteonecrosis after open reduction did not differ between patients treated after the age of 12 months compared with those treated at or before 12 months (OR, 1.1; 95% CI, 0.7-1.9; p = 0.7). The incidence of osteonecrosis (≥ Grade II) was 18.3% (95% CI, 11.7%-27.4%) among patients who had index open reduction at or before 12 months of age and 20.0% (95% CI, 13.1%-29.4%) among those who had index open reduction after 12 months of age. Among hips treated with open reductions, there was no difference in osteonecrosis after medial versus anterior approaches (18.7% medial versus 19.6% anterior; OR, 1.1; 95% CI, 0.5-2.2; p = 0.9). Conclusions We did not find an association between closed or open reduction performed at or before 12 months of age and an increased risk of osteonecrosis of the femoral head. Delayed treatment past 1 year of age as a strategy to reduce the development of osteonecrosis was not supported by this meta-analysis. Open reduction through a medial or anterior approach may be recommended based on surgeon's preference, because we found no association between development of osteonecrosis and the type of surgical approach. However, many of the studies in the current literature are nonrandomized Level III or IV observational studies of inconsistent quality. Higher quality evidence is needed to better understand the effects of age at reduction and operative approach on the development of osteonecrosis after DDH treatment. Level III, therapeutic study.

Risk of osteonecrosis in patients taking bisphosphonates for prevention of osteoporosis: a systematic review and meta-analysis

We aimed to systematically review observational studies evaluating use of bisphosphonates (BPs) and risk of osteonecrosis of jaw (ONJ) or other sites among non-cancer patients. PubMed, EMBASE, and Cochrane Library were screened from database inception to Dec 2012. Two reviewers independently identified cohort and case-control studies evaluating the use of oral or intravenous (IV) BPs and the risk of ONJ and extracted the characteristics of the studies and risk estimates. Pooled estimates of odds ratios and 95 % confidence intervals (CI) were derived by random effects meta-analysis. Subgroup analyses were carried according to patients' characteristics and route of BP use. We identified 12 studies, including 2,652 cases and 1,571,997 controls. Use of BPs was associated with a significantly increased risk of ONJ or ON of other sites [odds ratio (OR) 2.32; 95 % CI 1.38-3.91; I (2) = 91 %]. The summary OR was 2.91 (95 % CI 1.62-5.22; I (2) = 85.9 %) for adjusted studies. Use of BPs were associated with higher risk on ONJ (OR 2.57; 95 % CI 1.37-4.84; I (2) = 92.2 %) than ON of other sites (OR 1.79; 95 % CI 0.71-4.47; I (2) = 83.3 %). Meta-regression analysis did not find design characteristics or outcome definitions to be significant sources of heterogeneity. The available evidence suggests that use of BPs in cancer patients is associated with a substantial risk for ONJ. Patients receiving IV BP are at highest risk.

The importance of a thorough medical and pharmacological history before dental implant placement

The risk of osteonecrosis in patients treated with bisphosphonates is well known and guidelines intended to prevent this complication have been established and accepted. Bisphosphonate related osteonecrosis of the jaws (BRONJ) is a unique condition in which even past administration of medication may be of current and future relevance. We present a case of BRONJ in the maxilla after dental implant placement. The patient suffered from osteoporosis and had been treated with oral alendronate sodium in the past. However, the medication was stopped two years before implant placement, and the treating dentist was unaware of the patient's past bisphosphonate use. Prevention of BRONJ is based on identifying at-risk patients, and then avoiding or modifying dentoalveolar surgical procedures in these individuals. Nevertheless, there seems to be some difficulties identifying patients at risk. We present some of the challenges that impede thorough assessment of a patient's medical background (review of systems) in the dental office, and suggest possible solutions.

한국인에서 HMG-CoA reductase 유전자다형성과 대퇴골두무혈성괴사증과의 연관성 분석

Osteonecrosis of the femoral head (ONFH) is a multifactorial disease and certain individuals are more at risk or may be predisposed to it. An altered lipid metabolism is one of the major risk factors for osteonecrosis, especially corticosteroid therapy and alcoholism. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statin used as lipid-clearing agent, have been known to decrease the risk of osteonecrosis in patients receiving steroids and affect coagulation and fibrinolysis. Therefore we evaluated the association of HMG-CoA reductase gene polymorphisms and haplotypes between osteonecrosis patients and normal controls. We directly sequenced the HMG-CoA reductase gene in 24 Korean individuals, and identified five sequence variants. Four SNPs (-6933C＞T, -6045T＞G, +12673G＞A, and +18128C＞T) were selected and genotyped in 349 male ONFH patients and 300 male control subjects. The genotypes, allele frequencies, and haplotypes of the polymorphisms in the total patients as well as in the subgroup by etiology were not significantly different from those in the control group. In addition, no significant differences between each genotype of the polymorphisms and plasma lipid level could be found in the control group. These results suggest that the polymorphisms and haplotypes of HMG-CoA reductase gene are unlikely to be associated with a susceptibility to ONFH.

Bisphosphonate osteonecrosis of the jaws; an increasing problem for the dental practitioner

Osteonecrosis of the jaws is an increasingly recognised complication of bisphosphonate therapy. Although this has generated a large amount of literature in the last few years, it is difficult to know how the complications associated with bisphosphonates are impacting on general dental practitioners (GDPs). Bisphosphonates are commonly prescribed in the management of osteoporosis, hypercalcemia and multiple myeloma. The risk of osteonecrosis in patients taking bisphosphonates is low but difficult to quantify. The risk associated with oral therapy is in the order of 0.01% although with parenteral therapy it may be as high as 10%. Associated factors in the development of osteonecrosis include poor dental health, odontogenic infection and invasive dental treatment. Guidelines on managing patients who are currently taking or have previously taken bisphosphonates have not yet been published in the UK. The management of patients relies on existing experience in managing patients with apparently similar conditions such as osteoradionecrosis. Most GDPs do not routinely make specific efforts to identify patients who have taken bisphosphonates, and as patients may be poor at providing such information voluntarily, it is likely that many patients are currently not identified when they attend general dental practice. The dental management of patients with a history of bisphosphonate treatment is based around prevention and minimally traumatic treatment. Failure to recognise these patients and manage them appropriately could contribute to the development of osteonecrosis, which can be very difficult to manage.

Oral sodium clodronate induced osteonecrosis of the jaw in a patient with myeloma

Bisphosphonate therapy has been shown to significantly reduce the incidence of skeletal complications in patients with myeloma. Several recent reports have described osteonecrosis of the jaw (ONJ) associated with bisphosphonates. These reports mainly demonstrate an association between ONJ and potent i.v. bisphosphonates. We report a case of ONJ in a patient with myeloma, who had only been treated with oral sodium clodronate. While the degree of risk for osteonecrosis in patients taking oral bisphosphonates, such as clodronate, remains uncertain it would be prudent to consider carefully the indications for the use of these agents to minimise the risk of ONJ.

Jaw osteonecrosis in patients treated with bisphosphonates: MDCT evaluation

This study was done to evaluate the use of multidetector computed tomography (MDCT) in the evaluation of jaw osteonecrosis, a recently described medical entity in patients receiving long-term intravenous or oral bisphosphonates, and to help radiologists recognise it to enable early diagnosis and appropriate management. Thirty-eight patients with a history of neoplasm (breast, prostate, multiple myeloma, pancreas) or osteoporosis and bisphosphonate use and recent oral surgery who presented with pain in the mouth and temporomandibular joints, soft tissue infections, altered taste and numbness were examined with MDCT. In all patients, MDCT revealed the presence of structural bony alterations referable to osteonecrosis associated with orosinusal fistula in four of them and bony intraoral spicules in 25. Jaw osteonecrosis is an established medical entity discovered in patients who have undergone treatment with bisphosphonates and dental extraction or other oral surgery. MDCT with multiplanar (MPR), volume rendering (VR) and three-dimensional (3D) reconstructions allows accurate assessment of affected bone structures, enabling early diagnosis and suitable treatment planning. Radiologists should be aware of the risk of osteonecrosis in patients treated with bisphosphonates and be able to distinguish it from other bone diseases (osteomyelitis and osteoradionecrosis) with which it enters the differential diagnosis.

A SERPINE1 (PAI-1) Single Nucleotide Polymorphism Predicts Osteonecrosis in Children Treated for Acute Lymphoblastic Leukemia: Results of the Children's Oncology Group (COG) Study AALL03B2.

As intensity of glucocorticoid use has increased, osteonecrosis has become an increasingly frequent complication of modern intensive chemotherapy for pediatric patients with acute lymphoblastic leukemia (ALL). Although patient age > 10 years is a well-known risk factor, other host risk factors that may predispose to this complication are not well described. We tested whether 12 polymorphisms in 11 candidate genes were associated with osteonecrosis among up to 344 patients ≥ 10 years old treated on the Children's Cancer Group protocol CCG 1882 for newly diagnosed high-risk ALL, adjusting for gender, age, and treatment arm (augmented versus standard treatment). Genes tested (TYMS, ER, MTHFR, ABCB1, BGLAP (osteocalcin), ACP5, LRP5, ESR, SERPINE1, VDR, PTH, and PTHR) were chosen because they are candidates based on the putative mechanisms underlying osteonecrosis risk, including involvement in antifolate pharmacodynamics, drug pharmacokinetics, thrombosis risk, and possible hormonal influence on glucocorticoid effects. All children received dexamethasone during the delayed intensification phase of therapy, with doses varying by treatment arm (one dexamethasone pulse in the standard chemotherapy arm vs. two dexamethasone pulses in the augmented chemotherapy arm). Of the 11 candidate polymorphisms, a single nucleotide polymorphism (dbSNP rs6092) in the SERPINE1 gene (plasminogen activator inhibitor type 1 or PAI-1) was the only polymorphism associated with an increased risk of osteonecrosis in both univariate (p=0.0039) and multivariate (p=0.0019) analyses (adjusting for gender, age, and treatment arm), with an odds ratio of 2.51 (95% CI 1.32 to 4.74). Overall, 23.9% of the 88 children heterozygous or homozygous for the SERPINE1 T allele, versus 11.1% of the 234 children homozygous for the C allele, developed osteonecrosis. The combined CT or TT genotypes were present in a greater percentage (27%) of whites than in blacks (12%, p = 0.016), consistent with a higher risk (p = 0.003) of osteonecrosis in whites than blacks that was originally reported for CCG-1882 (J Clin Oncol 18:3262–72, 2000). In a multivariate analysis, only the SERPINE1 polymorphism and sex predicted AVN, with the incidence of osteonecrosis lower in boys (odds ratio 0.49, 95% confidence interval 0.25 to 0.96, p = 0.034). No statistically significant gene-gene interactions between SERPINE1 and any other tested genotype were noted. SERPINE1 polymorphisms and PAI-1 serum levels have previously been associated with a clinical pro-thrombotic state. We conclude that polymorphisms in SERPINE1 may contribute to the risk of osteonecrosis in patients treated with glucocorticoids.

Systematic Review: Bisphosphonates and Osteonecrosis of the Jaws

Osteonecrosis of the jaws is a recently described adverse side effect of bisphosphonate therapy. Patients with multiple myeloma and metastatic carcinoma to the skeleton who are receiving intravenous, nitrogen-containing bisphosphonates are at greatest risk for osteonecrosis of the jaws; these patients represent 94% of published cases. The mandible is more commonly affected than the maxilla (2:1 ratio), and 60% of cases are preceded by a dental surgical procedure. Oversuppression of bone turnover is probably the primary mechanism for the development of this condition, although there may be contributing comorbid factors. All sites of potential jaw infection should be eliminated before bisphosphonate therapy is initiated in these patients to reduce the necessity of subsequent dentoalveolar surgery. Conservative débridement of necrotic bone, pain control, infection management, use of antimicrobial oral rinses, and withdrawal of bisphosphonates are preferable to aggressive surgical measures for treating this condition. The degree of risk for osteonecrosis in patients taking oral bisphosphonates, such as alendronate, for osteoporosis is uncertain and warrants careful monitoring.

Statin Therapy Decreases the Risk of Osteonecrosis in Patients Receiving Steroids

Osteonecrosis is a devastating complication of systemic steroid use. Prolonged steroid use produces a hyperlipidemic state in most patients and puts them at risk for osteoporosis and osteonecrosis. The fat content within the femoral head increases, resulting in increased intracortical pressure that may lead to sinusoidal collapse and osteonecrosis. Statins are lipid-clearing agents that dramatically reduce lipid levels in blood and tissues. Statins are widely used to prevent cardiovascular disease and have been shown to reduce the adverse effects of steroids on lipid metabolism. The purpose of this study was to determine whether the use of statin drugs affects later development of osteonecrosis in patients receiving steroids. The records of 284 patients who were taking statin drugs at the time they were started on high dose steroids were examined to determine whether osteonecrosis had developed. The patients remained on statin drugs during the entire time of steroid exposure. Magnetic resonance imaging scans were used to verify the osteonecrosis unless it was visible by radiograph. After an average of 7.5 years (minimum followup, 5 years), only three patients (1%) from the group had osteonecrosis develop. This 1% incidence is much less than the 3% to 20% incidence usually reported for patients receiving high-dose steroids. Statins may offer some protection against having osteonecrosis develop when steroid treatment is necessary.