Long-term Oral Bisphosphonate Research Articles

Risk factors for development of Atypical Femoral Fractures in patients on long-term oral Bisphosphonate therapy

Risk factors for development of Atypical Femoral Fractures in patients on long-term oral Bisphosphonate therapy

Bone Quality and Fractures in Women With Osteoporosis Treated With Bisphosphonates for 1 to 14 Years.

ABSTRACTOral bisphosphonates are the primary medication for osteoporosis, but concerns exist regarding potential bone‐quality changes or low‐energy fractures. This cross‐sectional study used artificial intelligence methods to analyze relationships among bisphosphonate treatment duration, a wide variety of bone‐quality parameters, and low‐energy fractures. Fourier transform infrared spectroscopy and histomorphometry quantified bone‐quality parameters in 67 osteoporotic women treated with oral bisphosphonates for 1 to 14 years. Artificial intelligence methods established two models relating bisphosphonate treatment duration to bone‐quality changes and to low‐energy clinical fractures. The model relating bisphosphonate treatment duration to bone quality demonstrated optimal performance when treatment durations of 1 to 8 years were separated from treatment durations of 9 to 14 years. This may be due to a change in relationship of bone‐quality parameters with treatment duration. This model also showed that the effects of bisphosphonate treatment duration were most highly correlated with changes in means and standard deviations of infrared spectroscopically derived mineral and matrix parameters and histomorphometric bone turnover parameters. A second model related treatment duration to bone fracture in all 22 patients who fractured while on treatment with bisphosphonates for more than 8 years. This second model showed that bisphosphonate treatment duration, not hip bone mineral density (BMD), was the most strongly correlated parameter to these low‐energy bone fractures. Application of artificial intelligence enabled analysis of large quantities of structural, cellular, mineral, and matrix bone‐quality parameters to determine relationships with long‐term oral bisphosphonate treatment and fracture. Infrared spectroscopy provides clinically relevant bone‐quality information of which bone mineral purity is among the most relevant. Nine or more years of bisphosphonate treatment was associated with abnormal bone mineral purity, matrix abnormalities, and low‐energy fractures. These data justify limiting bisphosphonate treatment duration to 8 years. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Early changes in bone turnover and bone mineral density after discontinuation of long-term oral bisphosphonates: a post hoc analysis.

The short-term effects of discontinuing long-term bisphosphonates are poorly characterized. This post hoc analysis investigated 1-12-month changes in bone mineral density (BMD) and bone turnover markers (BTM) after alendronate (ALN) discontinuation. Data were from a randomized, double-blind trial of MK-5442 (calcium-sensing receptor antagonist) following oral bisphosphonates, with placebo and continued ALN controls ( ClinicalTrials.gov NCT00996801). Postmenopausal women with osteoporosis had received oral bisphosphonate (≥ 3-4 preceding years; ALN for the 12 months pre-screening), continuing on ALN 70 mg/week (n = 87) or placebo (n = 88). At 12 months, least-squares mean percent changes from baseline BMD (placebo vs. ALN) were lumbar spine (LS): - 0.36 vs. 1.29, total hip: - 1.44 vs. 0.46, and femoral neck (FN): - 1.26 vs. - 0.08 (all P < 0.05). BTM levels increased by 1-3 months, to 12 months, with placebo vs. ALN (P < 0.001). FN BMD decline was greater in the placebo subgroup with higher urinary N-terminal cross-linked telopeptides of type I collagen/creatinine [uNTx/Cr] (P < 0.01), and higher serum N-terminal pro-peptide of type 1 collagen [P1NP] levels (P < 0.05), at baseline. There was a trend toward greater FN BMD loss with higher BTM levels at 3 and/or 6 months. Younger age and higher LS BMD at baseline were associated with greater LS BMD loss at 12 months (P = 0.04 and < 0.01, respectively); higher baseline FN BMD predicted greater FN BMD loss (P = 0.04). Early changes in BTM levels and BMD were observed after discontinuation of long-term ALN. Further characterization of factors associated with patients' risk of bone loss upon bisphosphonate discontinuation is warranted.

Over half of seniors who start oral bisphosphonate therapy are exposed for 3 or more years: novel rolling window approach and patterns of use.

The purpose of this study was to identify and describe patterns of long-term oral bisphosphonate use among seniors using a novel methodological approach that considers extended follow-up. Among Ontarians aged 66years or older, we identified subjects with a first dispensing of alendronate or risedronate between November 2000 and December 2016. We followed them until death or December 2019 to identify patients with ≥ 3years of bisphosphonate use, defined as a proportion of days covered ≥ 80%, using 3-year rolling windows. We calculated the proportion of patients with long-term therapy (≥ 3years of use) using Kaplan-Meier estimates. We described patterns of long-term use and compared patient characteristics between patients with and without long-term therapy. We identified 260,784 eligible seniors initiating bisphosphonate therapy. Of these, 60% continued therapy ≥ 3years (77% women), and 48% continued ≥ 5years. Characteristics did not meaningfully differ between patients with or without long-term therapy. The median length of long-term therapy was 7.0 (IQR 5.1) years for women and 6.1 (IQR 4.3) years for men. Only 20% experienced a treatment gap before long-term therapy, yet 50% experienced a treatment gap of ≥ 120days after a median 5.3years of therapy. Eighty-one percent who returned to therapy following a treatment gap re-initiated an oral bisphosphonate, with 18% switching to denosumab. Among seniors initiating oral bisphosphonates, we found that 60% receive at least 3years of therapy when using an extended follow-up. Studies are needed to examine the benefits and harms of continuing bisphosphonate therapy beyond 3years.

Long-Term Oral Bisphosphonate Compliance Focusing on Switching of Prescription Pattern.

BackgroundFactors determining bisphosphonate compliance are not fully understood. We examined fluctuations in oral bisphosphonate dosing intervals to gauge therapeutic compliance in patients with osteoporosis.Materials and MethodsHospital data accruing between 2010 and 2017 were accessed to retrospectively study patients ≥50 years old (N=1873), each prescribed bisphosphonate at initial diagnosis of osteoporosis. The medication possession ratio (MPR), calculated as total days supplied divided by length of follow-up, served to measure therapeutic compliance. We compared MPRs of various prescription patterns (daily, weekly, monthly, and switch [ie, ≥1 change in pattern] groups). We also analyzed the impact of age, sex, fracture history, surgical history, and comorbidities. Multiple regression analysis was ultimately performed, using MPR as a dependent variable.ResultsIn our cohort (mean follow-up=5.7±2.4 years), once weekly dosing was the most common prescription pattern (1223/1873, 65.3%), as opposed to monthly (366/1873, 19.5%) or daily (164/1873, 8.8%) dosing. A total of 120 patients (6.4%) comprising the switch group changed dosing patterns during the study period. MPR was significantly higher in the switch group (32.8±22.7) than in the other three groups (daily, 21.9±25.9; weekly, 22.7±27.3; monthly, 23.2±27.7). In multiple regression analysis, younger age (P<0.001), female sex (P=0.004), and switching of prescription pattern (decrease or increase frequency) were factors significantly associated with higher MPR, signaling better compliance.ConclusionBetter bisphosphonate compliance was associated with physician-modified dosing patterns. We therefore recommend adjustments of prescription intervals in poorly compliant patients requiring long-term treatment.

Adherence to osteoporosis therapy after an upper extremity fracture: a pre-specified substudy of the C-STOP randomized controlled trial.

To compare the effectiveness of two interventions on long-term oralbisphosphonate adherence after an upper extremity fragility fracture. Community-dwelling participants 50years or older with upper extremity fragility fractures not previously treated with bisphosphonates were randomized to either a multi-faceted patient and physician educational intervention (the active control arm) vs. a nurse-led case manager (the study arm). Primary outcome was adherence (taking > 80% of prescribed doses) with prescribedoral bisphosphonates at 12months postfracture between groups; secondary outcomes included rates of primary non-adherence and 24-month adherence. We also compared quality of life between adherent and non-adherent patients. By 12months, adherence with the initially prescribed bisphosphonate was similar (p = 0.96) in both groups: 38/48 (79.2%) in the educational intervention group vs. 66/83 (79.5%) in the case manager arm. By 24months, adherence rates were 67% (32/48) in the educational intervention group vs. 53% (43/81) in case managed patients (p = 0.13). Primary non-adherence was 6% (11 patients) in the educational intervention group and 12% (21 patients) in the case managed group (p = 0.07). Prior family history of osteoporosis (aOR 2.1, 95% CI 1.0 to 4.4) and being satisfied with current medical care (aOR 2.3, 95% CI 1.1 to 4.8) were associated with better adherence while lower income (aOR 0.2, 95% CI 0.1 to 0.6, for patients with income < $30,000 per annum) was associated with poorer rates of adherence. There were no differences in health-related quality of life scores at baseline or during follow-up between patients who were adherent and those who were not. While both interventions achieved higher oral bisphosphonate adherence compared to previously reported adherence rates in the general population, primary non-adherence and long-term adherence to bisphosphonates were similar in both arms. Adherence was influenced by family history of osteoporosis, satisfaction with current medical care, and income. ClinicalTrials.gov : NCT01401556.

Bone Turnover in Osteoporotic Women During Long-Term Oral Bisphosphonates Treatment: Implications for Treatment Failure and “Drug Holiday” in the Real World

Little data exist to support concerns over bone turnover suppression during prolonged oral bisphosphonate treatment and on consequences of the recommended "drug holiday." This study was performed to assess bone resorption rates in postmenopausal osteoporotic women on prolonged oral bisphosphonate treatment and in response to switching to "drug holiday" intravenous bisphosphonate, or continuation of oral bisphosphonates. The frequency distribution of the bone resorption marker urinary deoxypyridinoline crosslinks (uDPD), was obtained retrospectively from 211 osteoporotic women attended at an academic hospital endocrine clinic, treated for >2 years with oral bisphosphonates. In some patients, uDPD was re-assessed following modification or continuation of treatment. The mean duration of oral bisphosphonates treatment was 7.2 ± 3.1 years. uDPD was within reference range for premenopausal women in 61.6% of the patients, below in 7.6% of the patients, and above upper limit in 30.8%. uDPD decreased significantly following intravenous zoledronic acid, increased significantly during "drug holiday," and slightly decreased in those continued on oral bisphosphonate treatment. In this real-world study, the majority of women on prolonged oral bisphosphonates maintained bone resorption rates within the normal reference range for premenopausal women. The likelihood for inadequate suppression was considerably greater than that of over-suppression. Implementing a "drug holiday" resulted in a marked increase in bone resorption rates. Additional studies should explore the potential role of bone turnover markers in the evaluation of patients on prolonged oral bisphosphonates and during "drug holiday" in different settings and using additional markers. BMD = bone mineral density; IQR = interquartile range; uDPD = urinary deoxypyridinoline crosslinks.

Long-term oral bisphosphonate use in relation to fracture risk in postmenopausal women with breast cancer: findings from the Women's Health Initiative.

The aim of the study was to examine the association of long-term oral bisphosphonate use, compared with short-term use, with fracture risk among postmenopausal women with breast cancer. We studied 887 postmenopausal women who were enrolled to the Women's Health Initiative from 1993 to 1998, diagnosed with breast cancer after enrollment, and reported current oral bisphosphonate use of 2 years or more on a medication inventory administered in 2008 to 2009. The outcome of any clinical fracture was ascertained by self-report on an annual study form; a subset of fractures was confirmed with medical records. Women were followed from completion of the medication inventory until 2014. The association between duration of bisphosphonate use reported on the medication inventory and fracture was estimated using multivariate Cox proportional hazards survival models that compared 4 to 7 years and 8 or more years of bisphosphonate use with 2 to 3 years of use. On average, women were 76 years of age and were followed for 3.7 (SD 1.1) years. There were 142 clinical fractures. In the multivariate-adjusted analysis for fracture risk factors, 8 or more years of bisphosphonate use was associated with higher risk of fracture compared with 2 to 3 years of use (hazard ratio, 1.67 [95% CI, 1.06-2.62]). There was no significant association of 4 to 7 years of use with fracture. Bisphosphonate use of 8 or more years was associated with higher risk of any clinical fracture compared with 2 to 3 years of use. Our findings raise concern about potential harm or decreased effectiveness of long-term bisphosphonate use on fracture risk. The findings warrant confirmatory studies.

Switching of oral bisphosphonates to denosumab in chronic glucocorticoid users: A 12-month randomized controlled trial

ObjectivesTo evaluate the effect of switching from oral bisphosphonates to denosumab on bone mineral density (BMD) in long-term glucocorticoid users. MethodsAdult patients who were receiving long-term prednisolone (≥2.5mg/day for ≥1year) and oral bisphosphonates (≥2years) were recruited. Participants were randomized to either continue oral bisphosphonates or switch to denosumab (60mg subcutaneously every 6months) for 12months. Serial BMD (lumbar spine, hip) and bone turnover markers (serum osteocalcin, P1NP, β-CTX) were measured. Results42 women were recruited (age 54.7±12.9years; 21 shifted to denosumab and 21 continued on bisphosphonates). The duration of prednisolone therapy was 101±66.3months and the daily dose was 4.4±2.1mg. Baseline demographic data, osteoporosis risk factors, and BMD at various sites were similar between the two groups of patients. At month 12, BMD of the spine and hip increased by +3.4±0.9% (p=0.002) and +1.4±0.6% (p=0.03), respectively, in the denosumab group; whereas the corresponding change was +1.5±0.4% (p=0.001) and +0.80±0.5% (p=0.12) in the bisphosphonate group. The spinal BMD at month 12 was significantly higher in the denosumab than bisphosphonate group after adjustment for baseline BMD and β-CTX values, and other confounding factors (p=0.01). Bone turnover markers (β-CTX and P1NP) were more strongly suppressed by denosumab than the bisphosphonates. Minor infections were more common in denosumab-treated patients while other adverse events occurred at similar frequencies between the two groups. ConclusionsIn patients receiving long-term glucocorticoids, switching from oral bisphosphonates to denosumab resulted in greater gain of the spinal BMD and suppression of bone turnover markers after 12months of therapy. The results have to be confirmed by a larger clinical trial with fracture as endpoint.

Adherence to oral bisphosphonates and the risk of subtrochanteric and femoral shaft fractures among female medicare beneficiaries.

Previous studies have shown an association between duration of bisphosphonate use and atypical femur fractures. This cohort study showed an increasingly higher risk of subtrochanteric and femoral shaft fractures among those who were more adherent to oral bisphosphonates. Long-term use of oral bisphosphonates has been implicated in an increased risk of atypical femur fractures located in subtrochanteric and femoral shaft regions. Another measure of drug exposure, medication adherence, however, has not been investigated. Among all Medicare fee-for-service female beneficiaries from 2006-2010, we followed 522,287 new bisphosphonate users from their index prescription until being censored or having a primary diagnosis of closed subtrochanteric/femoral shaft or intertrochanteric/femoral neck fractures. Data about radiographs of fracture site and features were not available. Adherence was classified according to the medication possession ratio (MPR) as the following: MPR < 1/3 as less compliant, MPR ≥ 1/3- < 2/3 as compliant, and MPR ≥ 2/3 as highly compliant. Alternative cutoff points at 50 and 80% were also used. Survival analysis was used to determine the cumulative incidence and hazard of subtrochanteric/femoral shaft or intertrochanteric/femoral neck fractures. There was a graded increase in incidence of subtrochanteric/femoral shaft fractures as the level of adherence increased (Gray's test, P < 0.001). The adjusted hazard ratio (HR) for the highly compliant vs. the less compliant was 1.23 (95% Confidence Interval [CI] 1.06-1.43) overall, became significant after 2 years of follow-up (HR = 1.51, 95% CI 1.06-2.15) and reached the highest risk in the fifth year (HR = 4.06, 95% CI 1.47-11.19). However, age-adjusted incidence rates of intertrochanteric/femoral neck fractures were significantly lower among highly compliant beneficiaries, compared to less compliant users (HR = 0.69, 95% CI 0.66-0.73). Similar results were obtained when the cutoff points for being compliant and highly compliant were set at 50 and 80 %, respectively. Subtrochanteric/femoral shaft fractures, unlike intertrochanteric/femoral neck fractures, are positively associated with higher adherence to long-term (≥3 years) oral bisphosphonates in the elderly female Medicare population.

Improving Inter-Professional Communication among Medical and Dental Providers Treating Bisphosphonate Therapy Patients May Reduce the Risk of Osteonecrosis of the Jaw

While large clinical trials have shown rare adverse side effects in post-menopausal women taking uninterrupted oral bisphosphonates (BPs), there is mounting evidence that longer-term treatment may be associated with osteonecrosis of the jaw (ONJ). There is a paucity of information regarding the causal relationship between extended oral BP treatment and ONJ, and the safety of non-surgical therapy of apical lesions and length of treatment in women on long-term BPs. We describe a post-menopausal woman on long-term oral BPs who developed ONJ without any contributory risk factors. Quantitative data was gathered through review of the patient's medical record. Qualitative data was gathered from face-to-face interviews with patient and clinician. Analysis of the data revealed the patient did not feel it was important to report her use of BPs. Given the wide usage of antiresorptives dental clinicians should manage all post-menopausal women with the assumption they currently or have recently been treated with BPs. There is a need for a collaborative effort by medical and dental practitioners to reduce risk of ONJ, ensure proper BP dosing and length of treatment, identify contributory risk factors, and explore alternate modalities, such as Ca(OH)2 multi-visit palliative pulpectomy, to avert ONJ and improve treatment outcomes.

Bisphosphonate-Related Osteonecrosis of the Jaw at a Previously Grafted Sinus

It had been frequently reported that surgical trauma by implant surgery can be related with the onset of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Recently, a long-standing dental implant itself has also been reported to be a risk for the development of BRONJ. This article reports a case of development of BRONJ after long-term oral bisphosphonate (BP) administration and successful maxillary sinus augmentation with a xenograft and simultaneous dental implantation. Considering that the dental implant at the grafted sinus had been maintained successfully for a long period, the BRONJ in the present case was not related to surgical trauma but was regarded a spontaneous onset. The current case highlights the necessity of a long-term follow-up for BP patients with maxillary sinus augmentation for implant placement, even though the short-term progress after sinus surgery is normally uneventful.

Risk factors for development of atypical femoral fractures in patients on long-term oral bisphosphonate therapy

Bisphosphonates (BPs) are the first-line therapy for osteoporosis. In recent years, atypical femoral fractures (AFF) have been described in patients on BPs therapy. However, the relationship between BPs and AFF remains to be clarified. We evaluated clinical and hormonal characteristics of AFF patients, in order to determine AFF risk factors. We studied 11 females with AFF and 58 females with typical femoral fractures (TFF), admitted to our Department for surgical repair between January 2008 and December 2011. All AFF patients received BPs therapy for 6 to 13yrs, whereas 36.2% (p<0.0001) of TFF patients received BPs for shorter period (TFF, 6.1±1.8yr vs. AFF, 8.6±1.9yr, p<0.0001). A higher prevalence of hypocalcemia was observed in AFF patients compared with TFF (p<0.02), with significantly (p<0.05) lower corrected calcium levels in AFF patients. By contrast a reduced prevalence of elevated PTH levels (p<0.05) was found in AFF patients. No significant difference in prevalence of vitamin D defect was observed between the two groups. Younger age (p<0.004), higher BMI (>30kg/m2, p<0.03) and early menopausal age (p<0.05) were observed in AFF patients. At time of fracture, prevalence of osteopenia/osteoporosis and levels of bone turnover markers were significantly (p<0.01) lower in AFF compared with TFF patients. By multivariate analysis hypocalcemia, obesity, and younger age (<70yr) were confirmed to be independent predictors of AFF; elevated PTH level was the predominant independent protective factor (p<0.004). In conclusion, our data indicate that clinical characteristics and metabolic factors may favor the development of AFF in BP treated patients. We identified hypocalcemia due to latent hypoparathyroidism as primary risk factor for AFF; age, obesity, early menopause, and BMD may also influence the development of AFF. An adequate clinical and metabolic assessment is suggested to prevent the development of AFF in BP treated patients.

Atypical Femoral Fractures Shortly After Osteonecrosis of the Jaw in a Postmenopausal Woman Taking Alendronate for Osteoporosis

Bisphosphonates effectively increase bone mineral density and reduce fracture risk in patients with osteoporosis, but there are concerns about osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFFs) in the long-term users. So far both complications have not been reported as occurring simultaneously in an osteoporotic individual on oral alendronate. The aim of this study was to report a postmenopausal woman presenting with concomitant ONJ and AFF on oral alendronate treatment. SUBJECT, MEASURES, AND RESULT: The patient was a 63-year-old woman with a history of rheumatoid arthritis for 30 years and diabetes for 3 years. Spinal compression fractures at levels L3 and L4 were documented, and she took alendronate 70 mg weekly for 7 years. She is the first case whose dental periapical imaging and pelvic radiography documented her ONJ and AFF, which developed subsequently within 6 months. This case report supports the association of both ONJ and AFF with long-term oral bisphosphonate therapy.

Plain vitamin D or alfacalcidol as follow-up treatment of postmenopausal osteoporosis after continuous long-term once weekly bisphosphonate intake

ZusammenfassungEine langjährige orale Bisphosphonat (BP)– Behandlung der Osteoporose kann durch übermäßige Suppression des Knochenumbaues negative Effekte auf die Knochenqualität haben. Es gibt bislang keine verbindlichen Empfehlungen zur Anwendungsdauer der BP, aber eine Therapieunterbrechung nach etwa fünf Jahren wird heute überwiegend angeraten. Bezüglich anschließenden Folgebehandlung gibt es allerdings auch kaum publizierte wissenschaftliche Daten. Wir haben in einer zweijährigen Studie an 85 Frauen mit postmenopausaler Osteoporose nach einer mittleren BP-Einnahmedauer von 4,2 Jahren zwei verschiedene Folge behandlungen vergleichend untersucht: Gruppe A (n = 42) erhielt 800 IE natürliches Vitamin D + 1200 mg Kalzium pro Tag, Gruppe B (n = 43) 1 µg Alfacalcidol + 500 mg Kalzium pro Tag. Primärer Endpunkt war die Änderung der Knochenmineraldichte (BMD) nach 12 und 24 Monaten. Weitere Endpunkte waren neu auftretende Stürze und Frakturen, Rückenschmerz (VAS 0–10) und unerwünschte Therapieeffekte. Zwischen den beiden Gruppen bestanden keine Unterschiede in den Ausgangscharakteristika Alter, Body-Mass-Index, Größenverlust, BMD, Rückenschmerz-Score und der Anzahl vorbestehender Stürze und Frakturen. In Gruppe A änderten sich die BMD-Werte an der LWS nicht signifikant während der zwei Jahre Follow-up nach Absetzen der BPEinnahme. Dagegen zeigte sich in Gruppe B für die LWS ein signifikanter Anstieg von 2,1 % (B vs. A p &lt; 0,01). An den zwei Femurmessorten fanden wir leichte Abnahmen in der Vitamin-D-Gruppe und einen signifikanten Anstieg unter Alfacalcidol. Die mittlere Anzahl von Stürzen pro Patient blieb unverändert in Gruppe A und nahm signifikant ab in Gruppe B (p &lt; 0,05). Die Anzahl der Patienten mit neuen Wirbelfrakturen unterschied sich nach zwei Jahren nicht zwischen beiden Therapiegruppen, während die Inzidenz von nichtvertebralen Frakturen in der Alfacalcidol-Gruppe signifikant niedriger ausfiel (p &lt; 0,05). Des Weiteren fand sich eine signifikant stärkere Verminderung der Rückenschmerzen bei den Patienten unter Alfacalcidol- Behandlung. Bezüglich der Häufigkeit unerwünschter Wirkungen fand sich kein Unterschied zwischen den beiden Gruppen. Die Ergebnisse zeigen, dass eine Therapieumstellung nach langzeitiger BP-Anwendung bei postmenopausaler Osteoporose auf Alfacalcidol der Nachbehandlung mit natürlichem Vitamin D überlegen ist.

Accurate Approach in the Treatment of Oral Bisphosphonate–Related Jaw Osteonecrosis

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is not completely understood and difficult to treat. Even though the occurrence of BRONJ is mainly related to the therapy with intravenous bisphosphonates (BPs), this article reports a case of long-term oral BP use and BRONJ occurrence. In addition, a literature review provides some additional information about BPs, BRONJ, and also a guideline for the prevention and treatment of BRONJ stages. A 79-year-old patient presented intense and persistent pain, purulent secretion, and exposed bone at the right side of the lower jaw. Thus, she was submitted to anamnesis, radiologic and tomographic examinations, and bacterial culture and sensitivity tests. These procedures were followed by surgical debridement of the bone and surrounding tissues/cyst and antibiotic prescription and histopathologic analysis of the fragments. Together, the examinations performed showed the occurrence of stage 2 BRONJ. Moreover, the antibiotic prescription, discontinuation of oral BP, and surgical procedures ensure that the patient had no more symptoms. Therefore, considering the presented case, we believe that an accurate approach is promising to diagnose and treat stage 2 BRONJ and other associated pathologic findings.

Unusual case of a conservatively treated pathological fracture after sequestrectomy in a patient with long-term oral bisphosphonate use

Bisphosphonates are used in the management of metastatic bone disease, Paget’s disease of bone and osteoporosis. A long-term complication of these drugs is bisphosphonate-related osteonecrosis of the jaws (BRONJ). Treatment of BRONJ can be quite challenging, and remains a topic of debate. We report the case of a 74-year-old woman who had used Fosamax ® (alendronate sodium) orally for four years. After 3½ years she developed pain, swelling, and a fistula in the left mandible. After exploration and sequestrectomy in combination with antibiotic treatment, osteolysis with a pathological fracture developed. Given the extent of the disorder and a decrease in complaints after the surgery, a non-surgical approach was chosen with continuation of the antibiotic treatment for 10 weeks, a soft diet and not wearing of dentures. During follow-up complaints subsided, the intra-oral fistula disappeared and the fracture healed. This is the first report of healing of a BRONJ patient stage III with pathological fracture. It illustrates the remaining healing potential of the bisphosphonate-treated bone.

A Retrospective Clinical and Radiographic Study on Healing of Periradicular Lesions in Patients Taking Oral Bisphosphonates

Introduction Bisphosphonates have been related to impaired bone remodeling. The impact of oral bisphosphonates on periradicular healing has not been studied. The purpose of this study was to evaluate the healing of periradicular lesions in patients taking oral bisphosphonates after root canal therapy. Methods Thirty-four teeth with preoperative periradicular radiolucencies were identified in patients undergoing oral bisphosphonate therapy. These cases were examined clinically and radiographically to determine treatment outcome. Thirty-eight control teeth were selected from a pool of patients not taking bisphosphonates. Nonsurgical root canal treatment and retreatment was performed by endodontic residents and undergraduate dental students at Baylor College of Dentistry using nonstandardized protocols. Results In the bisphosphonate group, 73.5% of the lesions healed, whereas the control cases had a healing rate of 81.6%. There was no statistically significant difference between the groups (p > 0.05). Conclusion The results of this preliminary short-term study suggest that patients taking long-term oral bisphosphonates can expect a satisfactory outcome with evidence of periradicular healing after conventional root canal treatment. Thus, root canal treatment may be considered a safe and realistic alternative to extraction in patients on bisphosphonate therapy.

Whither goest the lifeless osteoclast?

Evaluation of: Weinstein RS, Roberson PK, Manolagas SC: Giant osteoclast formation and long-term oral bisphosphonate therapy. N. Engl. J. Med. 360, 53–62 (2009). Giant osteoclasts are pathognomonic in Paget’s Disease, secondary hyperparathyroidism, giant cell tumors and fibrous dysplasia. Weinstein et al. provided a detailed histological analysis of abnormal hypernucleated osteoclasts in half of a set of biopsies from patients who received clinical doses of alendronate, a bisphosphonate inhibitor of bone resorption. In addition, 30% of the osteoclasts were apoptotic, a feature not found in the other clinical conditions. Their report reveals new information about skeletal effects of alendronate in addition to known effects to inhibit osteoclastic bone resorption. Their report raises new questions about the lifecycle of the human osteoclast, effects of bisphosphonates on cell fusion and on efferocytosis (removal of apoptotic cells), significance, if any, of the abnormal osteoclasts, and distinguishing featu...

Clinical Investigation of C-Terminal Cross-Linking Telopeptide Test in Prevention and Management of Bisphosphonate-Associated Osteonecrosis of the Jaws

The aim of this study was to determine, in a clinical setting, the effectiveness of the C-terminal cross-linking telopeptide test (CTX) test in the prevention and management of osteonecrosis of the jaws (ONJ) in patients taking bisphosphonates. A total of 348 patients underwent a fasted morning CTX test. Of these, 222 were patients at risk of ONJ who had been referred for extractions, 15 had ONJ, and 113 were controls. The 215 patients taking long-term oral bisphosphonates were older (71 +/- 11.6 years), were predominantly women with osteoporosis, and were medically compromised. The average CTX value was 238 +/- 144 pg/mL, with 98 having a value less than 200 pg/mL. One patient with a CTX value of 126 pg/mL developed ONJ after an extraction. Seven intravenous bisphosphonate patients underwent extractions with no cases of ONJ developing. The CTX value was 329 +/- 354, with 4 less than 200 pg/mL. Fifteen patients developed ONJ, 12 after extractions and 3 spontaneously. Of these, 7, who were still taking a bisphosphonate at presentation, had a CTX value of 116 pg/mL. A CTX value of less than 150 pg/mL did not correlate with the clinical risk factors of age, gender, comorbidities, bone disease, or bisphosphonate duration. A statistically significant difference in the CTX value was found for those taking alendronate compared with those taking risedronate (P < .0001). If the bisphosphonate was ceased, the CTX value increased at approximately 25 pg/mL per month. The CTX test is not predictive of the development of ONJ for an individual patient but does identify those in the "risk zone," which is a value of less than 150 pg/mL to 200 pg/mL. If medically appropriate, the bisphosphonate can be ceased so that the CTX value increases to bring the patient out of the "risk zone."