History Of Bisphosphonate Therapy Research Articles

Hyperbaric oxygen therapy as a conservative approach for osteoradionecrosis of the jaw in an osteoporotic patient receiving oral bisphosphonate therapy: a case report

BackgroundOsteoradionecrosis of the jaw (ORNJ) is a well-known chronic side effect of radiotherapy (RT) for head and neck malignancies. Osteonecrosis of the jaw (ONJ), similar pathology to ORNJ, may be induced by bisphosphonate (BP) therapy and is known as BP-related ONJ (BRONJ). Although differences exist between ORNJ and BRONJ in terms of clinical features and management methods, ONJ in a patient with history of both RT and BP therapy is categorized as ORNJ in the diagnostic criteria, despite the possibility that the ONJ may be affected by BP considering the pharmacology and mechanism of action. To date, management of ORNJ with a history of BP therapy has been scarcely discussed.Case presentationWe report here our experience of serious ORNJ in an 82-year-old osteoporotic woman receiving oral BP therapy. She had undergone partial maxillectomy to treat left maxillary gingival cancer and had received RT of 60 Gy as postoperative treatment. She had a history of osteoporosis, for which she had been administered BP for 8 years and 5 months. A bony sequestrum 45 × 25 mm in size was found at the site of the mandibular ramus, and the clinical diagnosis was ORNJ. We administered hyperbaric oxygen therapy (HBOT), scheduled for 3–5 days per week in 2 courses, 35 times. After HBOT, we performed sequestrectomy avoiding invasive surgery such as mandibulectomy. After the surgical procedure the wound healed completely. Bone regeneration was confirmed by computed tomography postoperatively. There have been no signs of recurrence as of 4 years after the operation.ConclusionsWe undertook a multimodality approach with HBOT and conservative surgery and achieved a satisfactory outcome. HBOT may be worthy of consideration as a conservative approach for ORNJ in patients receiving BP therapy, leading to the possibility of avoiding invasive surgery such as mandibulectomy.

Dental Implants in A Patient with History of Zoledronate Therapy: A Challenging Case

Implant placement in patient with history of bisphosphonate therapy is still controversial due to the risks of osteointegration failure and Biphosphonate related osteonecrosis of the jaws. Very few cases are reported. This paper aimed to report the success at 3 years follow up of 4 implants placed in a female patient with history of breast cancer and zoledronate infu-sions ( twice yearly for 2 years).

233 BISPHOSPHONATES: ANOTHER COMPLEX DRUG TO PRESCRIBE

Abstract Background Bisphosphonates provide effective treatment for osteoporosis. They accumulate a bone reservoir lasting for 3 years and beyond. The 2021 NICE guidelines recommend a medication review and a ‘drug holiday’ after 5 years of oral bisphosphonate therapy for low-fracture risk patients. Continuing treatment for high risk individuals is advised: age=/>75, previous hip or vertebral fracture, one or more fractures during treatment, recent DEXA scan with T score =/<−2.5, and/or current treatment with oral glucocorticoids. This retrospective audit aimed to assess compliance with NICE guidelines in a primary care setting. Methods Data were collected using the Health One online medical record system in an urban general practice. Inclusion criteria: all patients =/> 65 years old, prescribed oral bisphosphonate therapy for osteoporosis for >5 years. Exclusion criteria: deceased, did not attend clinic >1 year, patients on bisphosphonate treatment for conditions other than osteoporosis. Results 137 patients with a history of bisphosphonate therapy were identified. 76 patients were on bisphosphonate treatment for greater than 5 years. Of the 76 patients, 33 were classified as low-fracture risk and appropriately commenced a drug holiday, while 22 correctly remained on bisphosphonates due to a high fracture risk. The remaining 21 patients inappropriately continued therapy without receiving a medication review, repeat DEXA or fracture-risk assessment. Conclusion One third of patients on bisphosphonates beyond 5 years were not assessed for a drug holiday. The aim of a bisphosphonate ‘drug holiday’ is to reduce poly-pharmacy and prevent rare but serious long-term adverse events (such as atypical fractures, osteonecrosis of the jaw, gastric cancer and atrial fibrillation). Factors which had an impact on inappropriate prescribing should be assessed. Incorporating computer-based prescribing alerts could support safe prescribing practices.

Treatment strategy for atypical ulnar fracture due to severely suppressed bone turnover caused by long-term bisphosphonate therapy: a case report and literature review

BackgroundAtypical fractures may occur due to the combined effect of severely suppressed bone turnover (SSBT) caused by long-term bisphosphonate treatment and chronic repetitive bone microdamage. Atypical fracture of the ulna due to SSBT is a rare entity; there is no standardized treatment strategy for this condition. We successfully treated a patient with atypical fracture of the ulna. Herein, we present this patient, review the relevant literature, and discuss the treatment strategy.Case presentationAn 84-year-old woman presented with atypical fracture of the left ulnar shaft due to SSBT. She had a history of bisphosphonate therapy (ibandronate and alendronate) since more than 10 years; her bone turnover was severely suppressed. We performed open reduction and internal fixation (ORIF) using dual plate with some additional treatments. These included drilling and decortication, use of autogenous bone graft, low-intensity pulsed ultrasound (LIPUS) treatment, and administration of teriparatide. Finally, bone union was observed at 11 months after surgery.ConclusionsBased on the literature review and our experience with this case, ORIF alone may not be adequate to achieve bone union; drilling, decortication, and use of cancellus bone graft is important to achieve favorable outcomes. Administration of teriparatide and LIPUS may facilitate early bone union, although further studies are required to provide more definitive evidence. Furthermore, ORIF using dual plate may help avoid implant failure owing to the long time required for bone union.

Saliva Acidity in Cancer Patients at Risk for MRONJ Receiving Long Term Bisphosphonate Therapy

Medication related osteonecrosis of the jaw (MRONJ) lacks a defined pathophysiologic mechanism, however, many mechanisms have been proposed including local tissue acidification within the jaws playing a key role in the pathogenesis of the disease [1]. Based on evidence that acidic environments result in the release of bisphosphonate (BP) from bone we sought to measure salivary pH levels in patients with MRONJ and compare these salivary pH levels against patients with resolved MRONJ lesions, patients with a history of BP therapy but without MRONJ and matched controls (no history of malignancy or BP exposure) [2]. We hypothesized that patients treated with bisphosphonate therapy for malignancy who subsequently developed MRONJ would have a more acidic oral cavity environment.

Management of patients attending for dental extractions with a history of bisphosphonate therapy; a service evaluation

Management of patients attending for dental extractions with a history of bisphosphonate therapy; a service evaluation

Intricate Assessment and Evaluation of Dental Implants in Patients on Bisphosphonate Therapy: A Retrospective Analysis.

Osteonecrosis is one of the prevalent side effects of bisphosphonate (BP) therapy in oral cancer patients. In case of patients with various oncologic lesions, standard guidelines contraindicate the use of dental implants if the patients are on BP therapy. Literature also quotes studies that emphasize on the safety of dental implants in patients on BP therapy. Hence, this study aimed to retrospectively evaluate the clinical outcome of dental implants in patients on BP therapy. In this retrospective analysis, a total of 140 dental implants in 112 patients were included. Inclusion criteria included only those patients who were on or had history of BP therapy. Calculation of implant failure and survival rate was done. Ten cases of implant failure occurred, giving a success rate of above 92%, which was comparable to the results found in previous studies in patients who were not on BP therapy. No significant risk of implant failure is seen in patients on BP therapy compared with other patients.

Delayed healing of lower limb fractures with bisphosphonate therapy.

Bisphosphonate therapy (BT) is used commonly in the management of osteoporosis. A systematic review was conducted investigating delayed union of lower limb, long bone fractures in patients on BT. We specifically assessed whether BT increases the risk of delayed union or non-union in lower limb, long bone fractures. A literature search was conducted in the PubMed and Embase™ on 4 November 2014. Articles that investigated lower limb fractures, history of BT and fracture union were included in the review. A total of 9,809 papers were retrieved and 14 were deemed suitable for this review. The mean time to union in patients on BT was 8.5 months. A longer time to union was reported in a study investigating BT users versus controls (6.5 vs 4.8 months respectively). The mean rate of delayed or non-union for BT associated atypical fractures was 20% per fracture. Specifically in one study, delayed union was more common in the cohort with more than three years of BT (67%) than in the group with less than three years of BT (26%). Surgical fixation was associated with improved outcomes compared with non-operative management. BT has been described to be associated with multiple adverse outcomes related to atypical fractures. Current evidence recommends operative management for this patient group. Further investigation is required to evaluate the exact effects of BT on lower limb fractures, in particular typical femoral fractures.

Oral microbiota and host innate immune response in bisphosphonate-related osteonecrosis of the jaw.

Bacterial biofilms have emerged as potential critical triggers in the pathogenesis of bisphosphonate (BP)-related osteonecrosis of the jaw (ONJ) or BRONJ. BRONJ lesions have shown to be heavily colonized by oral bacteria, most of these difficult to cultivate and presents many clinical challenges. The purpose of this study was to characterize the bacterial diversity in BRONJ lesions and to determine host immune response. We examined tissue specimens from three cohorts (n=30); patients with periodontal disease without a history of BP therapy (Control, n=10), patients with periodontal disease having history of BP therapy but without ONJ (BP, n=5) and patients with BRONJ (BRONJ, n=15). Denaturing gradient gel electrophoresis of polymerase chain reaction (PCR)-amplified 16S rRNA gene fragments revealed less bacterial diversity in BRONJ than BP and Control cohorts. Sequence analysis detected six phyla with predominant affiliation to Firmicutes in BRONJ (71.6%), BP (70.3%) and Control (59.1%). Significant differences (P<0.05) in genera were observed, between Control/BP, Control/BRONJ and BP/BRONJ cohorts. Enzyme-linked immunosorbent assay (ELISA) results indicated that the levels of myeloperoxidase were significantly lower, whereas interleukin-6 and tumor necrosis factor-alpha levels were moderately elevated in BRONJ patients as compared to Controls. PCR array showed significant changes in BRONJ patients with downregulation of host genes, such as nucleotide-binding oligomerization domain containing protein 2, and cathepsin G, the key modulators for antibacterial response and upregulation of secretory leukocyte protease inhibitor, proteinase 3 and conserved helix–loop–helix ubiquitous kinase. The results suggest that colonization of unique bacterial communities coupled with deficient innate immune response is likely to impact the pathogenesis of ONJ.

Osteonecrosis of the Jaw Onset Times Are Based on the Route of Bisphosphonate Therapy

Osteonecrosis of the jaw (ONJ) has been reported to be associated with patients receiving bisphosphonate (BP) therapy. There are many reports that suggest that the time of exposure to BPs is a significant risk factor for ONJ and that the greatest risk occurs after dentoalveolar surgery. The aim of this study was to retrospectively investigate the duration of BP therapy and related events before the onset of ONJ based on an intravenous (IV) or oral route of administration. We conducted a retrospective cohort study of patients referred to our institution to identify the onset of ONJ based on the exposure to BP therapy and associated triggers (ie, dentoalveolar surgery or spontaneous occurrence) based on the route of BP administration. Demographic data (ie, age, gender, and race), medical diagnosis related to BP therapy, and information as to whether the BP therapy was continued at the time of ONJ diagnosis were also collected. We reviewed the records for 114 patients with a history of ONJ. We divided patient cohorts by route of BP administration, with 76 patients having a history of IV BP therapy and 38 patients having a history of oral BP therapy. The overall onset of ONJ was earlier in the IV BP group (median, 3 years) compared with the oral BP group (median, 5 years). There was no statistical difference in the duration to occurrence of ONJ associated with dental extraction compared with spontaneous occurrence for both the IV and oral BP groups. The median onset of ONJ for patients undergoing IV BP therapy occurs earlier than the median onset for patients undergoing oral BP therapy, and there was no difference in onset occurring spontaneously and after dental extraction. The significance of these findings suggests that patients who receive IV BP therapy should be closely evaluated after the initiation of BP therapy. The lack of evidence suggesting greater onset after dental extraction may provide clinical support for dentoalveolar surgery that is indicated for patients with a history of BP therapy. Research focusing on the clinical circumstances and physiologic events during early antiresorptive therapy may provide insight as to the critical risk factors.

Association of Low-energy Femoral Shaft Fractures and Bisphosphonate Use

The purpose of this study was to elaborate on the association between the use of bisphosphonates and low-energy femoral shaft fractures. A retrospective review was performed between January 2000 and January 2010 to identify patients older than 65 years who sustained femoral shaft diaphyseal fractures (Orthopaedic Trauma Association classification 32 A [extra-articular], B [partial articular/unicondylar], or C [complete articular/bicondylar]) using ICD-9 code 821.01. After exclusion criteria were applied, 77 patients remained for analysis. A total of 66 patients had no history of bisphosphonate therapy, and 11 patients had received bisphosphonate therapy for >2 years prior to admission. All 11 patients in the bisphosphonate group had sustained a low-energy fall from a standing height or lower. In 9 of 11 (82%) patients in the bisphosphonate group, radiographs resembled transverse shaft fractures with lateral cortical beaking that have been observed in patients on chronic bisphosphonate therapy.Our series echoes the findings of other authors, who found that bisphosphonate use is associated with lateral cortical beaking and low-energy, transverse fractures of the femoral shaft. Further research is needed to determine if specific medications and length of treatment are important risk factors.

Implant Placement in Patients with Oral Bisphosphonate Therapy: A Case Series

Although the effect of bisphosphonates on dental implant osseointegration is not clear, dental implant failures attributable to oral bisphosphonate therapy have been reported in patients with osteoporosis. The aim of this study was to evaluate implant survival in patients with a history of bisphosphonate therapy in a retrospective survey. A total of 46 ITI implants placed in 21 osteoporotic patients (females; average age 53 years, range 42-79 years) were evaluated with regard to probing depth, mobility, thread exposure, and bleeding on probing. All patients were under oral bisphosphonate therapy. None of implants showed mobility and all patients could be considered free from peri-implantitis. Time of bisphosphonate therapy before and after implant insertion showed no statistically significant influence on PD, BOP, and TE. Likewise, implant location, prosthetic type, and opposing dentition had no statistically significant influence on the clinical and radiological parameters of implants. Within the limitations of this study, it could be concluded that neither being on oral bisphosphonate treatment before implant placement nor starting bisphosphonate therapy after implant installation might jeopardize the successful osseointegration and clinical and radiographic condition of the implants.

Predicting risk for bisphosphonate-related osteonecrosis of the jaws: CTX versus radiographic markers

The most common risk factor for bisphosphonate-related osteonecrosis of the jaws (BRONJ) is dentoalveolar surgery. It has been suggested that reduced serum C-terminal telopeptide (CTX) can determine the degree of osteoclast suppression and may predict the development of BRONJ after dentoalveolar surgery. Although there are many radiographic appearances associated with BRONJ, there are little data that describes changes preceding dentoalveolar surgery. The objective of this retrospective study was: 1) to investigate if reduced serum CTX values (i.e., <150 pg/mL) were associated with BRONJ after dentoalveolar surgery; and 2) to determine if specific radiographic changes are associated with teeth that develop BRONJ after extraction. A retrospective review of radiographic and/or serum CTX data was performed for 68 patients with a history of bisphosphonate therapy who either underwent dental extraction or were diagnosed with BRONJ in the Department of Oral and Maxillofacial Surgery during the period 2007-2009. Postoperative healing was assessed for 26 patients with reduced serum CTX levels (<150 pg/mL) who either underwent dental extraction or treatment for BRONJ. Preoperative radiographs were evaluated for 55 patients who either healed normally or developed BRONJ after dental extraction. All 26 patients (100%) who had serum CTX levels <150 pg/mL healed successfully after dentoalveolar surgery (20 patients) or after treatment for BRONJ (6 patients). Among the 55 patients who underwent radiographic evaluation, 24 patients (83%) with BRONJ exhibited periodontal ligament (PDL) widening associated with extracted teeth, whereas only 3 patients (11%) who healed normally demonstrated PDL widening. These data suggest that radiographic PDL widening may be a more sensitive indicator than CTX testing in predicting risk of BRONJ. Current guidelines that recommend minimal surgical intervention may need to be revised to include alternative strategies for the elimination or management of this pathology.

Histopathologic findings in bone from edentulous alveolar ridges: A Role in Osteonecrosis of the Jaws?

Bisphosphonate-related osteonecrosis of the jaws (BONJ) is characterized by a breach in the oral mucosa with exposure of necrotic bone. Although bisphosphonates impact multiple biologic processes, including bone turnover and vascularity, factors contributing to the pathogenesis of BONJ remain poorly understood. In this retrospective analysis, the histopathologic findings from 154 alveolar bone specimens obtained during osteotomy preparation for dental implant placement were reviewed from 147 consecutively treated patients [male (79); female (68); Caucasian (141); African-American (6)]. The alveolar ridge sites had been edentulous for 1 year or longer. None of the patients in this study had a history of bisphosphonate therapy or clinical evidence of BONJ. Two pathologists, masked, using predetermined criteria, reviewed and substantiated the pathology reports provided by the licensed pathology service. In selected cases, special stains had been conducted to help establish the presence of bacteria. The histopathologic findings for the core specimens were as follows: 76 viable bone (49.4%); 54 nonviable bone (35.0%); and 24 osteomyelitis (15.6%). These histopathologic findings indicate that the edentulous jaw can contain regions of nonviable bone and microbial biofilm formation for 1 year or more after tooth extraction and mucosal healing. Regions of necrotic bone and subclinical infection may contribute to the development of untoward clinical events, such BONJ and early implant failure.

Bisphosphonate-related Osteonecrosis of the Jaw: A Pictorial Review

Bisphosphonate-related osteonecrosis of the jaw (ONJ) is characterized by nonhealing exposed bone in the maxillofacial region in patients who have undergone bisphosphonate treatment. The underlying etiology is unclear and may be multifactorial. The diagnosis is primarily clinical. Diagnostic tissue sampling may exacerbate the process and is typically avoided, necessitating other diagnostic approaches. The appearance of ONJ at diagnostic imaging is variable and includes sclerotic, lytic, or mixed lesions with possible periosteal reaction, pathologic fractures, and extension to soft tissues. There is a spectrum of signal intensity changes on T1- and T2-weighted magnetic resonance (MR) images with variable enhancement, findings that may correspond to the clinical and histopathologic stage of the process. Bone scintigraphy is sensitive with increased uptake in the area of the lesion. Although the imaging findings are nonspecific, there appears to be a role for imaging in the management of ONJ. Radiography is relatively insensitive but typically employed as the first line of radiologic investigation. Computed tomography and MR imaging are more precise in demonstrating the extent of the lesion. A number of imaging modalities have revealed lesions that may be associated with bisphosphonate exposure in asymptomatic individuals or in the context of nonspecific symptoms. The risk of these lesions advancing to overt clinical disease is unknown at this time. The radiologist should be aware of ONJ and include it in the differential diagnosis when evaluating patients with a history of bisphosphonate therapy without jaw irradiation, so as to avoid potentially harmful biopsies.

Sinus Tracts—An Early Sign of Bisphosphonate-Associated Osteonecrosis of the Jaws?

Bisphosphonate-associated osteonecrosis of the jaw (BONJ) is defined as the presence of exposed bone for at least 8 weeks in patients with exposure to bisphosphonates and no history of radiotherapy to the jaw. We report 5 patients with a history of bisphosphonate use, sinus tracts or deep periodontal pockets and radiographic findings typical for BONJ but with no evidence of exposed necrotic bone at the first evaluation visit. The mean age was 70 years (range 66-77) and all were males. Patients had multiple myeloma (2), multiple myeloma and prostate cancer (1), monoclonal gammopathy of unknown significance (1) and osteoporosis (1). Three cases involved the mandible and 2 the maxilla. Four patients were on intravenous pamidronate and/or zoledonic acid and 1, alendronate. All cases except 1 (with deep periodontal pockets) presented with intraoral draining sinus tracts. Radiographic findings included persistence of extraction socket (2), mottled radio-opacity and radiolucency (1), presence of sequestrum (1) and no significant findings (1). Subsequently, 4 patients developed exposed bone and 1 patient had necrotic bone removed from the jaws. We report 5 patients with a history of bisphosphonate therapy where 4 patients had persistent sinus tracts and a fifth, severe bone loss. Four patients had radiographic findings typical for BONJ, and all subsequently developed necrotic bone. We propose modifying the definition of BONJ to include a category of "suspected BONJ" Stage 0(sa) where patients have persistent sinus tracts or localized deep periodontal pockets and typical radiographic findings for BONJ but are asymptomatic, and Stage 0(ss) for those who are symptomatic.

Dental Management of Patients With a History of Bisphosphonate Therapy: Clinical Dilemma

Bisphosphonate osteonecrosis, BON, was recently described in the literature. Lack of scientific evidence explaining the pathophysiologic mechanisms involved in the development of this oral complication has generated uncertainties about proper management of patients treated with a bisphosphonate. This manuscript discusses the dental management of two breast cancer patients treated with intravenous bisphosphonates as part of their cancer management and who developed oral disease. Clinical management decisions will be presented as well as the treatment outcomes.

Osteonecrosis of the jaws and bisphosphonates

Osteonecrosis of the jaws associated with bisphosphonate therapy was first identified in 2003 as a condition typified by exposed bone that does not heal after 8 weeks. Other signs and symptoms, such as pain and infection, may or may not be present. There is a strong need for consensus on a case definition for this condition. This condition has occurred primarily among cancer patients treated with the aminobisphosphonates zoledronic acid and pamidronate. The etiology of this condition remains unknown; however, oral disease and trauma appear to be important risk factors. This condition appears to be rare in metabolic bone disease and Paget's disease, with an estimated prevalence of approximately 1 per 100,000 person-years. Thus, the benefits of bisphosphonate therapy appear to outweigh the risks. Recommendations have been established for the oral health management of patients with a history of bisphosphonate therapy.

Treatment of Avascular Osteonecrosis of the Mandible in Cancer Patients With a History of Bisphosphonate Therapy by Combining Bone Resection and Autologous Platelet-Rich Plasma: Report of 3 Cases

Treatment of Avascular Osteonecrosis of the Mandible in Cancer Patients With a History of Bisphosphonate Therapy by Combining Bone Resection and Autologous Platelet-Rich Plasma: Report of 3 Cases

Safety of zoledronic acid in patients who have previously received bisphosphonate therapy

8156 Background: Because pamidronate was the previous standard of care for patients with bone involvement from breast cancer, many patients will be treated with zoledronic acid after exposure to pamidronate. Therefore, it is important to demonstrate that switching patients from pamidronate to zoledronic acid will not result in an increase in bisphosphonate-related side effects. A phase IV study was conducted to examine the benefits of zoledronic acid on pain palliation and quality of life and to assess the overall and renal safety profile of zoledronic acid in patients with breast cancer, prostate cancer, and multiple myeloma with or without a history of bisphosphonate therapy. Methods: Zoledronic acid (4 mg) was administered via 15-minute infusion every 3 or 4 weeks for 6 infusions. Adverse events were recorded, and serum creatinine was measured before each infusion. Notable serum creatinine increases were defined as ≥ 0.5 mg/dL, if baseline was < 1.4 mg/dL; ≥ 1 mg/dL, if baseline was ≥ 1.4 mg/dL; or as any doubling of serum creatinine. Adverse events and serum creatinine levels were reported by tumor type and history of bisphosphonate therapy. Results: Among 638 patients, 415 (65%) had received prior bisphosphonate therapy, primarily pamidronate (95.4%). Among 461 patients with pain at baseline, mean pain scores decreased significantly (P < .01) at every postbaseline assessment. The most frequent adverse events in all patient groups were fatigue, nausea, and arthralgia. Notable serum creatinine increases occurred in 6.3% of patients and were somewhat more common in patients with a history of bisphosphonate therapy (7.7%) versus bisphosphonate-naive patients (4.5%). Treatment delays from serum creatinine increase occurred in 1.5% of patients with prior bisphosphonate exposure and 0.5% of bisphosphonate-naive patients. However, elevations in serum creatinine and treatment delays did not correlate with duration of prior bisphosphonate therapy or tumor type. Conclusions: Zoledronic acid (4 mg via 15-minute infusion) is safe and well tolerated in patients who have received prior bisphosphonate therapy, regardless of therapy duration. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals Corp. Novartis Pharmaceuticals Corp. Novartis Pharmaceuticals