Duration Of Bisphosphonate Therapy Research Articles

Bisphosphonates and the risk of atypical femur fractures.

Bisphosphonates are effective in reducing hip and other fractures. However, concerns about atypical femur fractures (AFFs) have contributed to substantially decreased bisphosphonate use, and hip fracture rates may be increasing. Despite this impact, important uncertainties remain regarding AFF risks including the association between bisphosphonate use and other risk factors such as BMD, age, weight, and race. To address this evidence gap, a cohort study of 196,129 women ≥50years of age in the Southern California Kaiser Permanente HMO women (with ≥1 bisphosphonate prescription) were studied; the primary outcome was radiographically-adjudicated AFF between 2007 and 2017. Risk factors including bisphosphonate use and race were obtained from electronic health records. Multivariable Cox models were used for analysis. Benefit-risk was modeled for 1-10years of bisphosphonates to compare fractures prevented vs. AFFs associated. Among 196,129 women, 277 (0.1%) sustained AFFs. After multivariable adjustment, AFF risk increased with longer bisphosphonate duration: hazard ratio (HR) increased from HR=8.9 (95%CI: 2.8,28) for 3-5years to HR=43.5 (13.7138.1) for >8years. Hip BMD, surprisingly, was not associated with AFF risk. Other risk factors included Asian ancestry (HR=4.8 (3.6, 6.6)), short stature, overweight, and glucocorticoid use. Bisphosphonate discontinuation was associated with rapid decrease in AFF risk. Decreases in osteoporotic and hip fractures risk during 1-10years of bisphosphonates far outweighed the increase AFF risk in Caucasians, but less so in Asians. In Caucasians, after 3years 149 hip fractures were prevented with 2 AFFs associated compared to 91 and 8 in Asians. The evidence for several potential mechanisms is summarized with femoral geometry being the most likely to explain AFF risk differences between Asians and Caucasians. The results from this new study add to the evidence base for AFF risk factors and will help inform clinical decision-making for individual patients about initiation and duration of bisphosphonate therapy and drug holidays.

Atypical Femur Fracture in the Setting of Long-Term Bisphosphonate use for Osteogenesis Imperfecta: A Case Report

Bisphosphonate (BP) therapy for moderate to severe osteogenesis imperfecta (OI) has become a mainstay of treatment in the last three decades. Given the significant improvements in bone mineral density and theoretical reductions in fracture risk, many patients are treated with bisphosphonates for prolonged periods of time. There currently lacks consensus in the optimal duration of BP therapy for patients with OI, and patients are often treated on a case-by-case basis. Long-term BP therapy has been associated with atypical femur fractures in adult patients treated for osteoporosis. The American Society for Bone and Mineral Research concluded that the median duration of BP therapy in patients with atypical femur fractures was 7 years. The role of long-term BP therapy in OI patients with atypical femur fractures remains unclear. Here, a case report is presented of an adolescent patient with type V OI that sustained a subtrochanteric femur fracture with features of an atypical pattern following treatment with intravenous pamidronate for 10.5 years. At the time of injury, the contralateral femur was also found to have atypical features suggestive of an impending fracture. The completed fracture was treated with closed reduction and cephalomedullary nail fixation. The impending fracture was prophylactically stabilized using the same technique. Prior to the injury, limb-length radiographs obtained to evaluate lower extremity alignment demonstrated features of an impending fracture but went unnoticed. Further studies are needed to clarify the role of long-term BP therapy in patients with OI suffering from atypical femur fractures.

Long-term outcomes of prolonged bisphosphonates more than 2 years in bone metastatic breast cancer: risk vs benefit.

Bisphosphonates are the mainstay therapeutic options for prevention of skeletal-related events and generally used for up to 2 years in bone metastatic cancer patients. We aimed to evaluate the long-term outcomes of prolonged (> 2 years) bisphosphonate usage in bone metastatic breast cancer (BMBC) patients. Ninety-nine BMBC patients who had prolonged bisphosphonates were evaluated retrospectively for long-term outcomes and survival rates. Median duration of bisphosphonate therapy was 46.8 (24-198) months. Seven patients had bisphosphonate-related adverse events (osteonecrosis of the jaw (ONJ) (n = 6), ONJ and renal failure (n = 1)). Bisphosphonate was switched to another one because of bone metastasis progression in more than one-third of the patients (n = 36, 36.3%). The patients who had bisphosphonate switch therapy had statistically significant longer overall survival (p < 0.01). Neither duration nor type of bisphosphonates had effect on frequency of bisphosphonate-related adverse events. Bisphosphonates might be prolonged for more than 2 years in BMBC patients with an acceptable toxicity profile. In addition, bisphosphonates switch therapy should be preferred in those with progressive bone metastasis since it might contribute to better survival despite bisphosphonates could not have been shown to have survival benefit in previous studies.

Rare adverse effects of bisphosphonate therapy.

To give an update on the latest developments regarding rare adverse effects of bisphosphonate therapy. Recent studies covering osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFFs) provided several updates to the literature. Identification of ONJ in large population databases is a challenge but based on one systematic review, the ICD-10 diagnosis code K10.2 (inflammatory conditions of the jaw) seems to be the most commonly used code for this condition. Duration of bisphosphonate therapy was determined to be an important predictor of AFFs. Appropriate duration of therapy followed by a timely drug holiday was shown to be the best strategy for improving bone mineral density and reducing fracture risk, while minimizing risk of rare adverse effects of therapy. The utility of bone turnover markers as a monitoring tool during drug holidays needs to be further investigated. ONJ and AFFs are two of the rare adverse effects associated with bisphosphonate therapy. Population-level trends of bisphosphonate use suggest a decline in prescriptions, pointing to broad fears of these side effects. Careful patient evaluation, duration of bisphosphonate therapy, and use of drug holidays can help limit any risk associated with therapy.

Time to onset of bisphosphonate-related osteonecrosis of the jaws: a multicentre retrospective cohort study.

Osteonecrosis of the jaw (ONJ) is a potentially severe adverse effect of bisphosphonates (BP). Although the risk of ONJ increases with increasing duration of BP treatment, there are currently no reliable estimates of the ONJ time to onset (TTO). The objective of this study was to estimate the TTO and associated risk factors in BP-treated patients. Retrospective analysis of data from 22 secondary care centres in seven countries relevant to 349 patients who developed BP-related ONJ between 2004 and 2012. The median (95%CI) TTO was 6.0 years in patients treated with alendronate (n=88) and 2.2years in those treated with zoledronate (n=218). Multivariable Cox regression showed that dentoalveolar surgery was inversely associated, and the use of antiangiogenics directly associated, with the TTO in patients with cancer treated with zoledronate. The incidence of ONJ increases with the duration of BP therapy, with notable differences observed with respect to BP type and potency, route of administration and underlying disease. When data are stratified by BP type, a time of 6.0 and 2.2years of oral alendronate and intravenous zoledronate therapy, respectively, is required for 50% of patients to develop ONJ. After stratification by disease, a time of 5.3 and 2.2years of BP therapy is required for 50% of patients with osteoporosis and cancer, respectively, to develop ONJ. These findings have significant implications for the design of future clinical studies and the development of risk-reduction strategies aimed at either assessing or modulating the risk of ONJ associated with BP.

Osteoporosis treatment: a missed opportunity.

Osteoporosis affects 1.2 million Australians and, in 2012, fractures due to osteoporosis and osteopenia in Australians aged over 50 years cost $2.75 billion. Even minor minimal trauma fractures are associated with increased morbidity and mortality. Despite increasing therapeutic options for managing osteoporosis, fewer than 20% of patients with a minimal trauma fracture are treated or investigated for osteoporosis, so under-treatment is extremely common. Fracture risk assessment is important for selecting patients who require specific anti-osteoporosis therapy. Post-menopausal osteoporosis is frequently due to an imbalance in bone remodelling, with bone resorption exceeding bone formation. Antiresorptive drugs reduce the number, activity and lifespan of osteoclasts, and include bisphosphonates, oestrogen, selective oestrogen receptor-modulating drugs, strontium ranelate, and the human monoclonal antibody denosumab. Teriparatide is the only anabolic agent currently available that stimulates osteoblast recruitment and activity; its antifracture efficacy for non-vertebral fractures increases with the duration of therapy for up to 2 years when it is associated with persisting increases in bone formation rate at the tissue level. Newer anabolic agents are imminent and include an analogue of parathyroid hormone-related protein, abaloparatide, and a humanised monoclonal antibody to an inhibitor of bone formation, romosozumab. Selection of anti-osteoporosis therapy should be individualised to patients, and the duration of bisphosphonate therapy has been covered in recent guidelines. The benefits of treatment far outweigh any risks associated with long term treatment. General practitioners need to take up the challenge imposed by osteoporosis and become champions of change to close the evidence-treatment gap.

Medication-Related Osteonecrosis of the Jaw Around Dental Implants: Implant Surgery-Triggered or Implant Presence-Triggered Osteonecrosis?

Dentoalveolar surgery including tooth extractions and dental implants placement is considered the major risk factor for developing medication-related osteonecrosis of the jaw (MRONJ).In this study, a patient series of MRONJ around dental implants were carefully analyzed to describe the findings and to assess the possible risk factors. Fifteen patients with peri-implant bone osteonecrosis were selected out of a group of 250 patients (6%). Patients were divided into 2 groups according to the temporal relationship. Group 1 (G1)-necrosis immediately after implant placement (from 2 to 10 months) and defined as "implant surgery-triggered" MRONJ. Group 2-necrosis distant (from 1 to 15 years) from implant placement and defined as "implant presence-triggered" MRONJ. Epidemiological and pharmacological variables were recorded as well as specific data about osteonecrosis and dental implants. G1 included 6 patients: 5 (83.4%) treated with oral bisphosphonates (BPs) for osteoporosis and 1 (16.6%) with intravenous BPs for breast cancer. Mean duration of BP therapy (BPT) was 83.7 months. G2 included 9 patients: 8 patients (88.89%) treated with intravenous BPs for malignant disease and 1 (11.11%) with oral BPs for osteoporosis. Data confirms that not only surgical insertion of dental implants is a potential risk factor for the development of osteonecrosis but also the presence itself of the implant into the bone can be associated with this disease. Therefore, it is necessary to inform of the increased risk for MRONJ also the patients who have already osteointegrated implants and are going to start the BPT.The risk is lower for patients receiving oral BPs but it exists and seems to be higher if the implant is located in the posterior areas, if the duration of BPT is more than 3 years and if the patient is under corticosteroid therapy.

2016 American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice Guidelines on Postmenopausal Osteoporosis

The 2016 American Association of Clinical Endocrinologists/American College of Endocrinology Guidelines for postmenopausal osteoporosis provides comprehensive guidance on the diagnosis, evaluation and treatment of postmenopausal osteoporosis. A new diagnostic criterion which expands the diagnosis to patients with osteopenia and a high Fracture Risk Assessment Tool score has been added to the old diagnostic criteria. Recommendations on duration of bisphosphonate therapy are clearly outlined and are based on fracture risk stratification. The accompanying algorithm, which goes through all the steps from diagnosis to treatment and follow up is a handy guide for clinicians.

Serum Markers of Bone Turnover and Angiogenesis in Patients With Bisphosphonate-Related Osteonecrosis of the Jaw After Discontinuation of Long-Term Intravenous Bisphosphonate Therapy

To analyze serum markers of bone turnover, angiogenesis, endocrine function, and inflammation in patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ) who discontinued long-term intravenous bisphosphonate (BP) therapy. Serum samples were obtained from 25 BRONJ patients who had discontinued long-term intravenous BP therapy for an average of 11.4 ± 8.7 months and 48 non-BRONJ controls who continued receiving intravenous BP therapy. Samples were analyzed for total alkaline phosphatase, bone-specific alkaline phosphatase, osteocalcin, C-telopeptide, vascular endothelial growth factor, triiodothyronine, thyroxine, thyroid-stimulating hormone, 25-hydroxyvitamin D, and C-reactive protein. The mean number of BP infusions was significantly higher in BRONJ patients compared with controls (38.4 ± 26.3 infusions vs 18.8 ± 7.2 infusions, P < .0001); however, the duration of BP therapy was not significantly different between the groups (P = .23). Overall, there were no significant differences in any of the markers between BRONJ patients and controls (all P values ≥ .16). In a subgroup analysis that matched BRONJ patients and controls according to mean age and number of BP infusions (10 BRONJ patients and 48 controls), log10 vascular endothelial growth factor (2.9 ± 0.4 pg/mL vs 2.4 ± 0.4 pg/mL, P < .001) and C-reactive protein (34 ± 26 mg/L vs 13 ± 8 mg/L, P < .01) levels were significantly higher in BRONJ patients compared with controls. Within BRONJ patients, none of the serum markers were correlated with duration of BP discontinuation. Levels of bone turnover and endocrine markers in BRONJ patients who discontinue long-term intravenous BP therapy are similar to those in non-BRONJ controls receiving intravenous BP therapy. However, levels of angiogenesis and inflammation markers are higher in BRONJ patients who discontinue long-term intravenous BP therapy. The prolonged skeletal half-life of BPs may suppress bone turnover markers in BRONJ patients for several years after discontinuation of intravenous BP therapy, suggesting an extended effect on bone homeostasis.

Myeloma bone disease: pathogenesis, current treatments and future targets.

Patients with myeloma develop localized and generalized bone loss leading to hypercalcaemia, accelerated osteoporosis, vertebral wedge fractures, other pathological fractures, spinal cord compression and bone pain. Bone loss is mediated by a variety of biological modifiers including osteoclast-activating factors (OAF) and osteoblast (OB) inhibitory factors produced either directly by malignant plasma cells (MPCs) or as a consequence of their interaction with the bone marrow microenvironment (BMM). Raised levels of OAFs such as receptor activator of nuclear factor-kappa B ligand (RANKL), macrophage inflammatory protein 1 alpha, tumour necrosis factor-alpha and interleukin 6 stimulate bone resorption by recruiting additional osteoclasts. Via opposing mechanisms, increases in OB inhibitory factors, such as dickkopf-1 (Dkk-1), soluble frizzled-related protein-3 and hepatocyte growth factor (HGF), suppress bone formation by inhibiting the differentiation and recruitment of OBs. These changes result in an uncoupling of physiological bone remodelling, leading to myeloma bone disease (MBD). Moreover, the altered BMM provides a fertile ground for the growth and survival of MPCs. Current clinical management of MBD is both reactive (to pain and fractures) and preventive, with bisphosphonates (BPs) being the mainstay of pharmacological treatment. However, side effects and uncertainties associated with BPs warrant the search for more targeted treatments for MBD. This review will summarize recent developments in understanding the intimate relationship between MBD and the BMM and the novel ways in which they are being therapeutically targeted. All data included were sourced and referenced from PubMed. The clinical utility of BP therapy is well established. However, there is general acknowledgement that BPs are only partially successful in the treatment of MBD. The number of skeletal events attributable to myeloma are reduced by BPs but not totally eliminated. Furthermore, existing damage is not repaired. It is widely recognized that more effective treatments are needed. There remains controversy concerning the duration of BP therapy. Whether denosumab is a viable alternative to BP therapy is also contested. Many of the new therapeutic strategies discussed are yet to translate to clinical practice and demonstrate equal efficacy or superiority to BP therapy. It also remains controversial whether reported anti-tumour effects of bone-modulating therapies are clinically significant. The potential clinical utility of bone anabolic therapies including agents such as anti-Dkk-1, anti-sclerostin and anti-HGF is becoming increasingly recognized. Further research effectively targeting the mediators of MBD, targeting both bone resorption and bone formation, is urgently needed. This should translate promptly to clinical trials of combination therapy comprising anti-resorptives and bone anabolic therapies to demonstrate efficacy and improved outcomes over BPs.

AB0813 Bisphosphonate Drug Holiday from Patient Perspective - Beliefs and Attitudes

BackgroundBisphosphonates are widely prescribed and highly effective at limiting the bone loss in senile osteoporosis in both men and women. Although they are generally well tolerated, potential adverse effects may...

Debating the duration of bisphosphonate therapy

Debating the duration of bisphosphonate therapy

Adherence with bisphosphonate therapy in US veterans with rheumatoid arthritis

Pharmacy Benefits Management program data for patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were linked with clinical data to determine bisphosphonate adherence and persistence among US veterans with rheumatoid arthritis (RA) and to determine factors associated with adherence. The primary outcome measures were the duration of bisphosphonate therapy and the medication possession ratio (MPR). Patients with an MPR <0.80 were classified as nonadherent. Potential covariates considered in the analysis included patient demographics, RA disease activity and severity parameters, and factors associated with osteoporosis risk. Associations of patient factors with duration of therapy and adherence were examined using multivariable regression modeling. Bisphosphonates were prescribed to 573 (41.5%) of 1,382 VARA subjects. The mean ± SD duration of therapy for bisphosphonates was 39.2 ± 31.4 months. A longer duration of therapy correlated with older age, more years of education, and dual x-ray absorptiometry testing. The mean ± SD MPR of VARA subjects for bisphosphonate therapy was 0.69 ± 0.28; 302 (52.7%) were nonadherent. In multivariate analyses, nonadherence with bisphosphonate therapy was associated with a longer duration of RA disease (odds ratio [OR] 1.02, 95% confidence interval [95% CI] 1.00-1.04) and duration of bisphosphonate therapy >32 months (OR 1.63, 95% CI 1.04-2.57). Whites were less likely to have a low MPR compared with nonwhites (OR 0.52, 95% CI 0.30-0.88). Nonadherence with bisphosphonates was common in this cohort of RA patients and was associated with nonwhite ethnicity, a longer duration of RA disease, and a greater duration of bisphosphonate therapy.

Incidence and Risk Factors of Bisphosphonate-Related Osteonecrosis of the Jaw in Multiple Myeloma Patients Having Undergone Autologous Stem Cell Transplantation

Background: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe complication of bisphosphonate therapy. Due to their long survival and subsequently high cumulative doses of bisphosphonates, multiple myeloma patients have the highest risk of developing BRONJ of all patients treated with bisphosphonates. The purpose of the present study was to evaluate the incidence and risk factors for BRONJ in multiple myeloma patients after high-dose chemotherapy and autologous stem cell transplantation (ASCT). Patients and Methods: We retrospectively analyzed the data of 120 multiple myeloma patients after high-dose chemotherapy and ASCT treated with bisphosphonates and assessed the incidence and risk factors of BRONJ. Results: Of the 120 patients, 23 (19%) developed BRONJ. 6 patients suffered several BRONJ events, resulting in a total incidence of 23%. The risk for BRONJ was significantly higher for patients with rheumatism and recent dental manipulations. Furthermore, the number of previous bisphosphonate rotations, the duration of bisphosphonate therapy, and the type and cumulative dose of bisphosphonate used were associated with the incidence of BRONJ. Conclusion: Our study is the first to determine the risk of BRONJ in a homogeneous group of multiple myeloma patients treated with high-dose chemotherapy and ASCT.

Recent Management Controversies in Osteoporosis

Osteoporosis is an important health concern that leads to significant morbidity for millions of Americans. Most recently, several areas of osteoporosis treatment have been debated, including calcium and vitamin D supplementation, duration of bisphosphonate therapy, and frequency of bone mineral density measurement. This article reviews the recent studies on these controversial topics and presents the current practice guidelines.

Bisphosphonate‐related osteonecrosis of the jaw: an overview

Bisphosphonates are widely used in the management of metastatic disease to bone and in diseases of altered bone turnover. Recently, multiple-case series and retrospective studies have established a relationship between necrotic bone lesions localized to the jaw and the use of chronic bisphosphonate therapy. This condition has been named bisphosphonate-related osteonecrosis of the jaw (BRONJ). To evaluate the potential risks associated with this new and emerging complication, stage-specific management strategies and guidelines have been developed. In view of the widespread use of chronic bisphosphonate therapy, the observation of an associated risk of osteonecrosis of the jaw should alert practitioners to monitor for this previously unrecognized complication and to reevaluate the indications for and the duration of bisphosphonate therapy in patients with osteopenia/osteoporosis and cancer. Morbidity associated with BRONJ might be prevented or reduced by implementing prevention strategies and establishing early diagnostic procedures. The current widespread use of bisphosphonates as an inhibitor of bone resorption is directly attributable to their efficacy in improving the quality of life for patients with metastatic bone cancer, osteoporosis, and Paget's disease.

Predicting skeletal complications in metastatic breast cancer raises challenges

Predicting skeletal complications in metastatic breast cancer raises challenges

Therapeutic Options in the Management of Myeloma Bone Disease

Advanced multiple myeloma is typically accompanied by osteolytic bone lesions resulting from heightened osteolytic activity of osteoclasts and decreased rates of osteogenesis by osteoblasts. Therefore, patients with myeloma bone disease are at increased risk for skeletal-related events (SREs) such as pathologic fracture, the need for radiotherapy or surgery to bone, spinal cord compression, and hypercalcemia of malignancy. Each of these can reduce patients' functional independence, quality of life, and survival. Radiotherapy and surgery are often used to palliate bone pain and to stabilize, repair, or prevent bone fractures. Bisphosphonates (BPs) may reduce the risk of SREs. In particular, clodronate, pamidronate, and zoledronic acid (ZOL) have demonstrated efficacy for delaying the onset of potentially life-threatening SREs. Overall, BPs have a well established tolerability profile. The introduction of BPs for multiple myeloma was practice-changing, and patients now experience far fewer serious fractures and hypercalcemia of malignancy. Ongoing studies will help further refine and optimize the timing and duration of BP therapy in patients with myeloma bone disease.

A SNP in CYP2C8 is not associated with the development of bisphosphonate-related osteonecrosis of the jaw in men with castrate-resistant prostate cancer

A single nucleotide polymorphism (SNP) in CYP2C8 (rs1934951), was previously identified in a genome-wide association study as a risk factor for the development of osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates (BPs) for multiple myeloma. To determine if the same SNP is also associated with the development of ONJ in men receiving BPs for bone metastases from prostate cancer, we genotyped 100 men with castrate-resistant prostate cancer treated with bisphosphonates for bone metastases, 17 of whom developed ONJ. Important clinical characteristics, including type and duration of bisphosphonate therapy, were consistent among those who developed ONJ and those who did not. We found no significant correlation between the variant allele and the development of ONJ (OR = 0.63, 95% CI: 0.165–2.42, P > 0.47). This intronic SNP in CYP2C8 (rs1934951) does not seem to be a risk factor for the development of bisphosphonate-related ONJ in men with prostate cancer. It is important to note that this is only the second study to investigate the genetics associated with BP-related ONJ and the first to do so in men with prostate cancer. More studies are needed to identify genetic risk factors that may predict the development of this important clinical condition.

Recent Management Controversies in Osteoporosis

Osteoporosis is a important health concern that leads to significant morbidity for millions of Americans. Most recently, several areas of osteoporosis treatment have been debated, including calcium and vitamin D supplementation, duration of bisphosphonate therapy, and frequency of bone mineral density measurement. This article reviews the recent studies on these controversial topics and presents the current practice guidelines.