Long-term Bisphosphonate Administration Research Articles

Zoledronic Acid Accelerates ER Stress-Mediated Inflammation by Increasing PDE4B Expression in Bisphosphonate-Related Osteonecrosis of the Jaw.

Long-term administration of bisphosphonates can lead to a significant side effect known as bisphosphonate-related osteonecrosis of the jaw (BRONJ). Although macrophage-mediated inflammation has been established as an important factor in BRONJ, the underlying mechanism remains elusive. In the current study, the roles of endoplasmic reticulum (ER) stress in zoledronic acid (ZOL)-induced inflammation were analyzed in macrophages, and the regulatory mechanism of ER stress activation was next investigated. An in vitro model of BRONJ was established by treating RAW264.7 cells with ZOL. The activation of ER stress was analyzed by western blotting and transmission electron microscopy, and inflammation was assessed by quantitative real-time PCR and enzyme-linked immunosorbent assay. ER stress was significantly activated in ZOL-treated macrophages, and inhibition of ER stress by TUDCA, an ER stress inhibitor, suppressed ZOL-induced inflammation in macrophages. Mechanistically, phosphodiesterase 4B (PDE4B) was significantly increased in ZOL-treated macrophages. Forced expression of PDE4B promoted ER stress and inflammation, whereas PDE4B knockdown decreased ZOL-induced ER stress and inflammation in macrophages. More importantly, PDE4B inhibitor could improve ZOL-induced BRONJ in vivo. These data suggest that ZOL accelerates ER stress-mediated inflammation in BRONJ by increasing PDE4B expression. PDE4B inhibition may represent a potential therapeutic strategy for BRONJ. Subsequent research should concentrate on formulating medications that selectively target PDE4B, thereby mitigating the risk of BRONJ in patients undergoing bisphosphonate treatment.

Current vision on mechanism of action of bisphosphonates. The effect of long-term administration of bisphosphonates on bone tissue (preclinical studies)

Osteoporosis (OP) is one of the common chronic diseases in the elderly, which requires long–term therapy. Bisphosphonates (BP) belong to the first-line choice medications for the treatment of OP, however, prolonged period of bisphosphonates use has been associated with increased risk of atypical femoral fractures (AFFs), medication-related osteonecrosis of the jaw (MRONJ) and the impact on fracture healing, which attracts increased attention to the current widespread use of them.The article presents the existing classes of BP according to their chemical structure and mechanism of action, differences in their antiresorptive potencies. The data of studies on animal models on the effect of BP on the mechanical properties of bone, fracture repair, as well as the development of MRONJ are presented.

Examination of Risk Factors and Expression Patterns of Atypical Femoral Fractures Using the Japanese Adverse Drug Event Report Database: A Retrospective Pharmacovigilance Study.

Atypical femoral fracture (AFF) is a rare complication related to the use of bisphosphonates (BPs). Herein, we analyzed the risk factors and onset patterns of AFF using the Japanese Adverse Drug Event Report database and reported the findings. First, the independent risk factors for AFF were gender (female), high body mass index, and medical history of osteoporosis, arthritis, and systemic lupus erythematosus (SLE). Drug-related risk factors for AFF included BPs (i.e., alendronic acid, ibandronic acid, etidronic acid, zoledronic acid, minodronic acid, risedronic acid), denosumab, prednisolone, lansoprazole, rabeprazole, exemestane, letrozole, eldecalcitol, and menatetrenone. Therefore, it appears that AFF is influenced by a combination of patient backgrounds and drugs, and that the risk of developing AFF is particularly high in patients with fragile bones (e.g., osteoporosis, arthritis, and SLE). Second, in the analysis of AFF onset patterns, the onset of AFF from BPs and denosumab took a long time (>1 year) to develop. Analysis using a Weibull distribution showed wear-out failure-type AFF onset for BPs and denosumab, and both osteoporosis and cancer patients with long-term administration of these drugs showed a tendency to have an increased risk of onset. AFF developed earlier in osteoporosis patients with long-term administration of BPs and denosumab than in cancer patients.

Effect and timing of parathyroid hormone analog administration for preventing medication-related osteonecrosis of the jaws in a murine model

The aim of this study was to investigate the effect and timing of recombinant human parathyroid hormone analog (PTH) administration for preventing medication-related osteonecrosis of the jaws (MRONJ) using a murine model. After standardized MRONJ induction using zoledronic acid and dexamethasone injections, 48 female Sprague-Dawley rats were divided into four groups according to the timing of PTH administration before or after dental extraction. Rats were euthanized 3 weeks after dental extraction, followed by clinical and histologic analyses. No clinical improvements were observed in the preoperative and postoperative PTH groups, compared to controls (p = 0.638 and 0.496, respectively). However, on histological analysis, the number of empty lacunae reduced significantly, and the number of blood vessels increased in the preoperative PTH group (p = 0.004 and 0.002, respectively). The postoperative PTH group did not show significant differences for empty lacunae and blood vessels compared to controls (p = 0.075 and 0.194, respectively). The reduction in the empty lacunae and the increase in the blood vessels in the preoperative PTH group were significant compared to other groups, suggesting more viable bone tissue in this group.In perspective, preoperative PTH use may represent a better prophylactic regimen for preventing the occurrence of MRONJ after traumatic dental or surgical procedures, especially in patients with a history of long-term bisphosphonate administration or at high risk of developing MRONJ. However, the findings should be proven in further studies on other animals followed by clinical trials.

Morphological and Morphometrical Analyses of Fracture-Healing Sites of an Atypical Femoral Fracture in Patients with and without Long-Term Bisphosphonate Treatment for Osteoporosis: A Report of Two Cases

Bisphosphonates have been the first drug of choice for osteoporosis in the recent years because of their known ability to suppress osteoclast activity. The adverse effect of long-term bisphosphonate administration in the fracture-healing process is controversial. The aim of our study was to observe not only morphology but also morphometry of the fracture site of atypical femoral fracture with and without long-term bisphosphonate administration, in a case study of two difficult-to-obtain human samples. The patients with insufficient healing of atypical femoral fracture were treated with valgus wedge osteotomy. Histomorphometrical analysis was performed in bone samples of fracture sites harvested during osteotomy. The thickness of the femoral cortex was measured in the fracture site and the adjacent, non-fracture site. A comparative analysis of the content of hypertrophic osteoclasts in fracture sites, shape and size of osteons, mass, and ratio of the woven bone to the total bone mass was performed, comparing bisphosphonate-treated and untreated samples. In bisphosphonate-treated samples, we observed femoral cortex thickening at the fracture site; the appearance of hypertrophic osteoclasts; decreased bone resorption surface, decreased osteoclast numbers on the bone resorption surface, and increased ratio of multinuclear osteoclasts; osteons were misshapen and thin; and the mass and ratio of the woven bone to the total bone mass were higher. This study demonstrated that long-term bisphosphonate administration can alter the morphological features of the fracture site compared to its physiological state.

Morphological profile of atypical femoral fractures: age‐related changes to the cross‐sectional geometry of the diaphysis

The use of bisphosphonates for osteoporosis patients has markedly decreased the incidence of femoral neck or trochanteric fractures. However, anti-osteoporosis drugs have been reported to increase the incidence of atypical femoral fractures, which involve stress fractures in the subtrochanteric region or the proximal diaphysis. In this study, the morphological characteristics of the cortical bone in human femoral diaphysis samples were analyzed from individuals who lived before bisphosphonate drugs were available in Japan. A total of 90 right femoral bones were arbitrarily selected (46 males and 44 females) from modern Japanese skeletal specimens. Full-length images of these femurs were acquired using a computed tomography scanner. An image processing method for binarization was used to calculate the threshold values of individual bones for determining their contours. The range between the lower end of the lesser trochanter and the adductor tubercle of each femur was divided at regular intervals to obtain 10 planes. The mean value of cortical bone thickness, periosteal border length, and the cortical cross-sectional area was evaluated for all planes. Moreover, the ratio of the area of the cortical bone to the total area of cross-section at the mid-diaphysis was calculated. A comparison between males and females demonstrated that most females had lower cortical bone area ratios at the mid-diaphysis. The femoral outer shape did not differ markedly according to age or sex; however, substantial individual differences were observed in the shape of the inner surface of the cortical bone. The cortical bone thickness and the cross-sectional area decreased with age in the femoral diaphysis; furthermore, in females, the decrease was higher for the former than for the latter. This may be due to a compensatory increase in the circumference of the femoral diaphysis. In addition, in about half of the subjects there was a discrepancy between the region with maximal value of the cortical bone thickness and that of the total cross-sectional area. Biological responses to mechanical stresses to the femoral diaphysis are thought not to be uniform. Bisphosphonates inhibit bone resorption and may promote non-physiological bone remodeling. Thus, a nonhomogeneous decrease in cortical thickness may be related to the fracture occurrence in the femoral diaphysis in some cases. Thus, long-term administration of bisphosphonates in patients with morphological vulnerability in the femoral cortical bones may increase the occurrence of atypical femoral fractures.

Clinical features and prognostic factors of pediatric spine giant cell tumors: report of 31 clinical cases in a single center

Giant cell tumors (GCTs) of the bone are benign but locally aggressive. Pediatric spine giant-cell tumors (PSGCTs) have been infrequently reported in the literature because of the rarity of the disease. The purpose of this study was to define the overall occurrence rate of PSGCTs among all spinal GCTs in our center and investigate the clinical features and prognostic factors of this rare disease. A retrospective review. Thirty-one PSGCT patients, screened from 226 patients with spine GCTs who received treatment in our center between 1998 to 2017. The clinical symptoms, neurologic status, radiologic manifestations, treatment, outcome, and complications were recorded and analyzed. The postoperative recurrence-free survival (RFS) rate was estimated by the Kaplan-Meier method. Factors with p values ≤.1 were subjected to multivariate analysis for RFS by proportional hazard analysis, among which p values ≤.05 were considered statistically significant. A total of 31 (31 of 226, 13.7%) PSGCTs patients (9 male and 22 female) were included in the study, with a mean age of 15.9 years and a mean follow-up period of 85.1 (median 84.0; range 12-221) months. The majority of patients (80.6 %) were 14-18 years of age. Recurrence was detected in 12 (38.7%) of the 31 patients. Univariate and multivariate analyses suggested that Jaffe grade II-III was an adverse prognostic factor for RFS, while total spondylectomy and bisphosphonate treatment were positive prognostic factors. Total en bloc spondylectomy (TES) is associated with excellent prognosis for PSGCTs, and total piecemeal spondylectomy is a viable alternative if total en bloc spondylectomy is unfeasible. Long-term bisphosphonate administration could significantly reduce the recurrence risk of PSGCTs. Denosumab treatment is recommended, especially for advanced PSGCTs. Jaffe grade II-III is an adverse prognostic factor for recurrence.

Symposium: Imaging modalities for drug-related osteonecrosis of the jaw (6), assessment of mandibular metabolism due to long-term administration of an anti-resorptive agent by bone scintigraphy (secondary publication)

SummaryIt is not yet known why anti-resorptive agent-related osteonecrosis specifically affects the jaw. Here we assessed changes in the bone metabolism of the mandible in response to long-term bisphosphonate (BP) therapy, and we compared the bone metabolism changes of the mandible with those of other bone sites using a quantitative analysis by bone scintigraphy. The region of interest was selected by identifying without an abnormal accumulation of the mandible, humerus, second and fourth lumbar vertebrae, iliac crest, intertrochanteric femur and diaphysis. Bone scintigraphy images were quantified using a value we termed the ‘bone uptake value (BUV)’. In the low-dose bisphosphonate (LBP) group (n = 21), the patients were undergoing osteoporosis treatment with low-dose BP. The high-dose BP (HBP) group consisted of 12 bone metastasis patients undergoing high-dose BP treatment. The Control group was 47 subjects with oral disease who had never been treated with an anti-resorptive agent. Our analyses demonstrated that with long-term BP administration, the bone metabolism of the iliac crest and intertrochanteric femur was suppressed but that of the mandible was enhanced. There was no significant difference in bone metabolism with either the low-dose BP or high-dose BP treatment. The effects of the long-term administration of BP were site-specific.

Zoledronic acid promotes TLR-4-mediated M1 macrophage polarization in bisphosphonate-related osteonecrosis of the jaw.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a detrimental side effect of the long-term administration of bisphosphonates. Although macrophages were reported to be an important mediator of BRONJ, the detailed potential mechanism of BRONJ remains unclear. Here, we reported an elevated TLR-4 expression in macrophages under action of zoledronic acid (ZA), resulting in enhanced M1 macrophage polarization and decreased M2 macrophage polarization both in vitro and in vivo. After inhibiting the TLR-4 signaling pathway, the activation of the TLR-4/NF-κB signaling pathway and the induction of NF-κB nuclear translocation and production of proinflammatory cytokines by ZA were suppressed in macrophages, thereby inhibiting M1 macrophage polarization. By utilizing the TLR-4-/- mice, development of BRONJ was markedly ameliorated, and M1 macrophages were significantly attenuated in the extraction socket tissues in the TLR-4-/- mice. Importantly, the systemic administration of the TLR-4 inhibitor TAK-242 improved the wound healing of the extraction socket and decreased the incidence rate of BRONJ. Taken together, our findings suggest that TLR-4-mediated macrophage polarization participates in the pathogenesis of BRONJ in mice, and TLR-4 may be a potential target for the prevention and therapeutic treatment of BRONJ.-Zhu, W., Xu, R., Du, J., Fu, Y., Li, S., Zhang, P., Liu, L., Jiang, H. Zoledronic acid promotes TLR-4-mediated M1 macrophage polarization in bisphosphonate-related osteonecrosis of the jaw.

Anti-osteoporotic drugs and energy metabolism.

Accumulating evidence indicates close and tight relationship between bone tissue and energy expenditure, especially glucose metabolism. In molecular mechanisms, osteocalcin secreted from osteoblasts, as a hormone, is demonstrated in mice to be involved not only in insulin secretion from islet β-cells but also in insulin resistance in adipose tissue. In addition, since signaling cascades in liver activated by RANK ligand has been shown to participate in augmentation of insulin resistance, pharmacological inhibition of RANK ligand for treatment of osteoporosis is speculated to improve insulin resistance in human. However, data from several clinical trials of ant-osteoporosis drugs have not supported an idea that they were clinically involved in glucose metabolism. Interestingly, some retrospective observational studies demonstrate that long-term administration of bisphosphonates may decrease the incidence of newly onset of type 2 diabetes, although mechanisms by which they do so are totally uncertain.

Bilateral atypical femoral fractures induced by a long-term administration of bisphosphonates: a case report

Bilateral atypical femoral fractures induced by a long-term administration of bisphosphonates: a case report

The utility of bone scintigraphy in the assessment of mandibular metabolism during long-term bisphosphonate administration

The duration of antiresorptive therapy is an important risk factor for medication-related osteonecrosis of the jaw. We performed a pilot study using quantitative analysis by bone scintigraphy to test the hypothesis that mandibular metabolism is affected by long-term bisphosphonate (BP) therapy. Our primary objectives were to assess changes in bone metabolism of the mandible in response to long-term BP therapy and compare the bone metabolism changes of the mandible with other bone sites. We compared the metabolic difference at the site in the mandible unaffected by disease, the humerus and the femur between 14 osteoporosis patients who were being treated with BP (BP group) and 14 patients who were not being treated with BP (control group) using a quantitative analysis and bone scintigraphy. Study endpoints were the mean and maximum bone uptake values (BUVs) quantified using bone scintigraphy images of the mandible, humerus and femur. Quantified images of the site in the mandible unaffected by disease had significantly higher mean and maximum BUVs compared to the controls (mean, 0.74 vs. 0.49, p=0.019; max., 1.29 vs. 0.85, p=0.009, respectively). The mean and maximum BUV of femur ROIs in the BP group were significantly lower than those in control patients (mean BUV, 0.23 vs. 0.30, p=0.039; max. BUV, 0.43 vs. 0.53, p=0.024, respectively). This is the first report of mandible changes in response to long-term BP treatment, using bone scintigraphy. The results using bone scintigraphy demonstrated that the bone metabolism of the intact mandible is affected by a long-term administration of BP.

The effects of bisphosphonate on the remodeling of different irregular bones in mice

We aimed to compare the effects of bisphosphonate on the remodeling of irregular bones (the jaw and ilium) in mice after trauma. To verify the feasibility of modeling osteonecrosis, 20 mice were injected intraperitoneally with zoledronate and dexamethasone (ZOL&DEX group), dexamethasone (DEX group), or phosphate-buffered saline (PBS) [control (CTR) group]. Mice then underwent extraction of the right maxillary first molar and creation of an artificial bony cavity in the ilium. Bone sections were stained with H&E for morphological studies. To further compare differences between the maxilla and the ilium caused by similar traumas, 80 mice were injected intraperitoneally with ZOL&DEX or PBS. Pathological progression at the injury sites was assessed at 1 day and at 1, 3, and 8 weeks after trauma using micro-computed tomography (CT), H&E and immunohistochemistry analyses, high-performance liquid chromatography-mass spectrometry, and enzyme-linked immunosorbent assay. Only the ZOL&DEX model group effectively developed osteonecrosis. Bony sequestra, osseous sclerosis, unhealed mucosa, and radiopaque alveolar bone were found in the maxilla. In the ilium, there was a lower frequency of osteonecrotic disease and osseous sclerosis, and less suppression of bone remodeling than in the maxilla following long-term bisphosphonate administration. Zoledronate levels were higher in the maxilla. ZOL&DEX treatment suppressed the levels of RANKL and IL-17, but induced an upregulation of osteoprotegerin and FAM20C in both bones. Accumulation of bisphosphonate may increase the incidence of osteonecrosis. The RANKL/OPG pathway and IL-17 and FAM20C cytokines play key roles in the progression of pathologically abnormal bone remodeling.

Treatment and Prognosis of Femoral Insufficiency Fracture Associated with Prolonged Bisphosphonate Use

Purpose: This study was conducted to investigate and identify an appropriate fracture treatment method by analyzing patients in whom a femoral incompetence fracture occurred after receiving a long-term bisphosphonate administration. Materials and Methods: The subjects of this study were 13 cases out of ten patients among those who had a history of receiving bisphosphonate for more than five years and had a fracture or an imminent fracture with a characteristic radiological finding in the femoral subtrochanteric region and the interfemoral region. The period of the drug administration, bone density, the existence of a prodromal symptom, and bilateral fracture were investigated. Results: In seven out of the 13 cases, the patients complained of painat the femoral and pelvic parts as a prodrome (53.8%), and three of them showed a bilateral fracture (30%). An imminent fracture with a prodrome was observed in six cases (46.2%); for three of these cases, a prophylactic fixture pexis was performed by inserting a metal nail into the medullary cavity, and in two out of these three, a complete fracture was found within 11 months on average (3 to 19 months). In the three prophylactic fixture pexis performed cases, no postoperative complications were found, and a radiological finding of concrescence was seen within one year after the operation. Among the nine operation performed cases after the fracture, non-union was found in two. Conclusion: In the patients who have received bisphosphonate for a long periodof time, a prodome may be a useful indicator of a fracture in the femoral subtrochanteric region and the interfemoral region; therefore, a careful observation is necessary. A prophylactic internal fixation is recommended for patients with imminent fracture with a prodome since they have a high risk of a complete fracture is high in them.

Sequential treatment with teriparatide and strontium ranelate in a postmenopausal woman with atypical femoral fractures after long-term bisphosphonate administration

Despite the existence of numerous case series, no evidenced-based medical management for atypical fractures associated with bisphosphonate (BP) treatment has been established. We report the outcome of teriparatide (TRP) administration followed by strontium ranelate (SR) in a woman with a complete and an incomplete contralateral atypical fracture of the femoral diaphysis (AFF) associated with BP treatment. The spontaneous complete AFF was managed with intramedullary nailing, discontinuation of BP and initiation TRP. Eleven months later, she suffered a contralateral incomplete AFF. At the completion of the TRP treatment, she had only slight discomfort in the femur with the incomplete AFF. BMD testing revealed increase of 7.61% at the lumbar spine (LS) and 0.8% at the hip. Following TRP, 1-year SR treatment resulted in further BMD increase of 9.2% at the LS and 1.4% in the hip, while she does not report any pain. Bone markers remain within the normal range. Our case indicates that sequential therapy with TRP and SR in cases of AFF might be a rational treatment option. However, there is a need for additional information concerning the effect of TRP and SR, given alone or sequentially, in these patients in order to incorporate these drugs into the management of AFF.

Teriparatide in the treatment of non-unions: Scientific and clinical evidences

IntroductionEach fracture has a failing risk which can lead to a non-union. Among the non-invasive strategies proposed to improve bone healing, also in non-union, the use of teriparatide, a drug for the treatment of the osteoporosis, has increasing supporting data. Experimental dataMany studies mainly on rats, but also on primates, demonstrate the positive effect on fracture healing of teriparatide, both in physiological and pathological conditions, with a more rapid evolution of the reparative callus. Clinical dataA double blinded randomized controlled study on wrist fractures demonstrated a positive effect, in term of healing speed, of teriparatide at the dose of 20 μg/day, but not at the higher dose of 40 μg/day. A prospectic randomized study on pelvic fractures showed a faster healing in teriparatide treated patients. The use of teriparatide in non-unions is reported as effective in numerous case report. The effect of teriparatide seems very useful in the non-unions consequent to an atypical femoral fracture after long-term administration of bisphosphonates. ConclusionsA conceivable positive effect of teriparatide on fracture healing is well-documented on animals, and very likely on humans, however further studies are needed to confirm these hopeful hypotheses.

Case of femoral diaphyseal stress fracture after long-term risedronate administration diagnosed by iliac bone biopsy

Bisphosphonate excessively inhibits bone resorption and results in pathological fracture of the femur or ilium. The subject of this study was administered risedronate for 7 years; we suspected an easy fracture of the femoral diaphysis. In this study, we report the results of this patient’s bone biopsy and bone morphometric analysis. A 76-year-old female patient presented with right femoral pain. Bone mineral density of the anteroposterior surface of the 2nd to 4th lumbar vertebrae (L2–L4) was decreased and levels of bone turnover markers were high. Therefore, we initiated treatment with risedronate. As she continued the medication, urinary levels of cross-linked N-terminal telopeptides of type I collagen and alkaline phosphatase (bone-type isozyme) were found to be within the normal ranges. After 7 years of administration, the patient experienced pain when she put weight on the right femur and right femoral pain while walking. Plain radiographic examination revealed polypoid stress fracture-like lesions on the right femoral diaphysis and on the slightly distal-lateral cortical bone. Similar lesions were observed on magnetic resonance imaging and bone scintigraphy. We suspected severely suppressed bone turnover. Bone biopsy was obtained after labeling with tetracycline, and bone morphometric analysis was performed. On microscopic examination, slight double tetracycline labeling was observed. The trabeculae were narrow, and the numbers of osteoblasts and osteoclasts were decreased. Further, rates of bone calcification and bone formation were slow. Hence, we diagnosed fracture as a result of low turnover osteopathy. Risedronate was withdrawn, and Vitamin D3 was administered to improve the bone turnover. At 6 months, abnormal signals on magnetic resonance imaging had decreased and her pain while walking or undergoing the stress test disappeared as well. Thus, long-term administration of bisphosphonates may lead to easy fracture, although bone turnover markers were observed to be within the normal range. During bisphosphonate administration, physicians need to monitor closely and treat their patients for any pain experienced in the femoral region while walking or undergoing a stress test.

Skeletal Biodistribution of Fluorescently Labeled Bisphosphonate is Anatomic Site-Dependent

Objectives. Long-term administration of bisphosphonates has been associated with bisphosphonate-related jaw osteonecrosis (ONJ). A potential etiologic factor is disproportionate concentration of bisphosphonate in the jaws, but it is unclear if regional biodistribution and bioavailability of bisphosphonates is site-dependent. We tested in rats the hypothesis that skeletal biodistribution and release of pamidronate (a nitrogen-containing bisphosphonate) is anatomic site-dependent.

The cytotoxic effects of three different bisphosphonates in-vitro on human gingival fibroblasts, osteoblasts and osteogenic sarcoma cells

IntroductionOsteonecrosis of the jaw (ONJ) is an emerging condition in patients undergoing long-term administration of bisphosphonates (BP) for the treatment of osteoporosis and hypercalcaemia associated with malignancy, multiple myeloma, and metastatic breast and prostate cancers. This is a follow-up study, its purpose was to examine the effects in-vitro of intravenous zoledronic acid (ZOL) and pamidronate (PAM) and oral alendronate (FOS) on the human oral cavity using gingival fibroblasts and osteoblasts cells and, in addition, osteogenic sarcoma cells (SaOS-2-cells). Materials and methodsHuman gingival fibroblasts, osteoblasts and SaOS-2-cells were seeded on multiple 6-well plates at a density of 5×105cells in a 4-week cell culture. Four different concentrations (1, 5, 10, 20μM) of each BP (ZOL, PAM, FOS) and pyrophosphate were used in this study. ResultsAll BP decreased collagen production and lowered cell proliferation in-vitro. ZOL was the component with most inhibitory effect. ConclusionThe findings in this study suggest that ZOL, PAM and FOS generally diminish cell proliferation and collagen production of human gingival fibroblasts, osteoblasts and SaOS-2-cells. The present follow-up study shows that not only ZOL and PAM but also FOS have a strong inhibitory effect on collagen production and cell survival in-vitro.

Long-term bisphosphonate usage and subtrochanteric insufficiency fractures

For over a decade, bisphosphonate administration has evolved and become the cornerstone of the prevention and treatment of fragility fractures. Millions of post-menopausal women have relied on, and continue to depend on, the long-acting, bone density-maintaining pharmaceutical drug to prevent low-energy fractures. In return, we have seen the number of fragility fractures decrease, along with associated costs and emotional benefits. However, with any drug, there are often concerns with side effects and complications, and this unique drug class is seeing one such complication in atypical subtrochanteric femoral fracture, counterproductive to that which it was designed to prevent. This has created concern over long-term bisphosphonate administration and its potential link to these atypical fractures. There is controversial evidence surrounding such a definitive link, and no protocol for managing these fractures. This review offers the latest information regarding this rare but increasingly controversial adverse effect and its potential connection to one of the most successful forms of treatment that is available for the management of fragility fractures.