Administration Of Alendronate Research Articles

Hydrogen Sulfide and Carbon Monoxide Protect Gastric Mucosa Compromised by Mild Stress Against Alendronate Injury.

BackgroundAlendronate is an inhibitor of osteoclast-mediated bone resorption, but its clinical utility is limited due to gastrointestinal complications including bleeding erosions.AimsWe studied whether potent vasodilators hydrogen sulfide (H2S) and carbon monoxide (CO) can protect against alendronate-induced gastric lesions in rats exposed to mild stress.MethodsThree series (A, B, and C) of Wistar rats received alendronate (150–700 mg/kg i.g., series A) with or without NaHS (5 mg/kg), H2S donor or CORM-2 (5 mg/kg) releasing CO administered i.g. 30 min before alendronate administration (series B) in rats exposed for 3 days before alendronate administration to mild stress (series C). The area of gastric lesions was assessed by planimetry, the gastric blood flow (GBF) was determined by H2-gas clearance technique, and H2S production via CSE/CBS/3-MST activity and the gastric expression of HO-1, HO-2, HIF-1α, NF-κB, iNOS, COX-2, IL-1β, TNF-α, GPx-1 and SOD-2 were analyzed by qPCR or Western blot.ResultsAlendronate dose-dependently produced gastric mucosal lesions and significantly decreased GBF, and these effects were exacerbated by mild stress. NaHS and CORM-2 significantly reduced the alendronate-induced gastric lesions in non-stressed and stressed animals, but only NaHS but not CORM-2 raised H2S production. NaHS and CORM-2 inhibited gastric expression of HIF-1α protein and HO-1, HIF-1α, NF-κB, COX-2, iNOS, IL-1β, TNF-α mRNAs but failed to affect those of HO-2, GPx-1, and SOD-2.ConclusionBoth H2S and CO released from their donors, NaHS and CORM-2, protect gastric mucosa compromised by stress against alendronate-induced gastric damage via mechanism involving downregulation of HIF-1α, NF-κB and proinflammatory factors COX-2, iNOS, IL-1β, and TNF-α.

Effects of drug discontinuation after short-term daily alendronate administration on osteoblasts and osteocytes in mice.

In order to determine whether osteoclastic bone resorption is restarted after withdrawn of bisphosphonates, we conducted histological examinations on murine osteoclasts, osteoblasts and osteocytes after discontinuation of a daily regimen of alendronate (ALN) with a dosage of 1mg/kg/day for 10days. After drug discontinuation, metaphyseal trabecular number and bone volume remained unaltered for the first 4days. Osteoclast number did not increase, while the number of apoptotic osteoclasts was elevated. On the other hand, tissue non-specific alkaline phosphatase-immunoreactive area was markedly reduced after ALN discontinuation. In addition, osteocytes showed an atrophic profile with empty lacunar areas during and after ALN treatment. Interestingly, as early as 36h after a single ALN injection, osteocytes show signs of atrophy despite the presence of active osteoblasts. Structured illumination microscopy system showed shortening of osteocytic cytoplasmic processes after drug cessation, suggesting a possible morphological and functional disconnection between osteocytes and osteoblasts. Taken together, it appears that osteoclastic bone resorption is not resumed after ALN discontinuation; also, osteoblasts and osteocytes hardly seem to recover once they are inactivated and atrophied by ALN. In summary, it seems that one must pay more attention to the responses of osteoblasts and osteocytes, rather focusing on the resuming of osteoclastic bone resorption after the ALN discontinuation.

Alendronate Attenuates Spinal Microglial Activation and Neuropathic Pain.

Many derivatives of bisphosphonates, which are inhibitors of bone resorption, have been developed as promising agents for painful pathologies in patients with bone resorption-related diseases. The mechanism for pain relief by bisphosphonates remains uncertain. Studies have reported that bisphosphonates could reduce central neurochemical changes involved in the generation and maintenance of bone cancer pain. In this study, we hypothesized that bisphosphonates would inhibit spinal microglial activation and prevent the development of hyperalgesia caused by peripheral tissue injury. We investigated the effects of alendronate (a nitrogen-containing bisphosphonate) on the development of neuropathic pain and its role in modulating microglial activation invivo and invitro. Intrathecal and intraperitoneal administration of alendronate relieved neuropathic pain behaviors induced by chronic constriction sciatic nerve injury. Alendronate also significantly attenuated spinal microglial activation and p38 mitogen-activated protein kinase (MAPK) phosphorylation without affecting astrocytes. Invitro, alendronate downregulated phosphorylated p38 and phosphorylated extracellular signal regulated kinaseexpression in lipopolysaccharide-stimulated primary microglia within 1hour, and pretreatment with alendronate for 12 and 24hours decreased the expression of inflammatory cytokines (tumor necrosis factor α, and interleukins 1β and 6). These findings indicate that alendronate could effectively relieve chronic constriction sciatic nerve injury-induced neuropathic pain by at least partially inhibiting the activation of spinal microglia and the p38 MAPK signaling pathway. Alendronate could relieve neuropathic pain behaviors in animals by inhibiting the activation of spinal cord microglia and the p38 MAPK cell signaling pathway. Therapeutic applications of alendronate may be extended beyond bone metabolism-related disease.

Effect of alendronate on the progression of periodontitis induced by Porphyromonas gingivalis and Fusobacterium nucleatum: a study in rats.

The study aimed to investigate the effect of alendronate (ALN) on the inhibition of alveolar bone loss in experimental periodontitis in Wistar rats. Periodontitis was induced by oral inoculation of Porphyromonas gingivalis with Fusobacterium nucleatum. The rats (n=80) were randomized as follows: negative control (n=10); positive control (n=10); ALN groups: test 8 (n=10), test 12 (n=10), and test 16 (n=10); and placebo groups: control 8 (n=10), control 12 (n=10), and control 16 (n=10). Two milligrams per kilogram of ALN or placebo was administered twice weekly for 8, 12, and 16weeks. Bone loss was determined by morphological and histological analyses. One independent, blinded examiner (ICC, 0.91) performed the measurements. The distance from the cement enamel junction to the alveolar bone crest of the second lower molar was measured: distal-vestibular (d), furca (f), mesial-vestibular (h), and area. Histometry was performed on the second contralateral molar. Sections (6μm) were used to determine the furcation bone area (A-FB). The following statistical analyses were conducted: Mann-Whitney and Kruskal-Wallis. PC group developed periodontitis (p<0.0001). Morphometric analysis determined that ALN was effective in T8 for linear measurements d, f, and h (p<0.05). No significant differences occurred at test 8, test 12, and test 16. Analysis of A-FB revealed no significant differences between the ALN and placebo groups at 8 and 16weeks (p>0.05). ALN was effective against bone loss in relation to A-FB after 12weeks (p<0.0001). According to the methodology used, the results suggest that oral administration of ALN could influence alveolar bone loss in rats submitted to experimental periodontitis. ALN could be a potential therapeutic approach when associated with periodontal treatment.

An evaluation of the effect of pulsed wave low-level laser therapy on the biomechanical properties of the vertebral body in two experimental osteoporosis rat models.

Osteoporosis (OP) increases vertebral fragility as a result of the biomechanical effects of diminished bone structure and composition. This study has aimed to assess the effects of pulsed wave low-level laser therapy (PW LLLT) on cancellous bone strength of an ovariectomized (OVX-d) experimental rat model and a glucocorticoid-induced OP (GIOP) experimental rat model. There were four OVX-d groups and four dexamethasone-treated groups. A group of healthy rats was used for baseline evaluations. The OVX-d rats were further subdivided into the following groups: control rats with OP, OVX-d rats that received alendronate, OVX-d rats treated with PW LLLT, and OVX-d rats treated with alendronate and PW LLLT. The remaining rats received dexamethasone and were divided into four groups: control, alendronate-treated rats, laser-treated rats, and laser-treated rats with concomitant administration of alendronate. PW LLLT (890 nm, 80 Hz, 0.972 J/cm(2)) was performed on the spinal processes of the T12, L1, L2, and L3 vertebras. We extracted the L1 vertebrae and submitted them to a mechanical compression test. Biomechanical test findings showed positive effects of the PW LLLT and alendronate administration on increasing bending stiffness and maximum force of the osteoporotic bones compared to the healthy group. However, laser treatment of OVA-d rats significantly increased stress high load compared to OVA-d control rats. PW LLLT preserved the cancellous (trabecular) bone of vertebra against the detrimental effects of OV-induced OP on bone strength in rats compared to control OV rats.

A comparative study between intravenous and oral alendronate administration for the treatment of osteoporosis.

It has recently been reported that bisphosphonates are the most common treatment for osteoporotic patients. However, they are many problems, including poor bioavailability and adherence, as well as adverse drug reactions. Therefore, intravenous administration of bisphosphonates has been developed to resolve these problems. In Japan today, alendronate and ibandronate have been approved for intravenous administration, and they have advantages, such as good adherence and better gastrointestinal tolerability, compared to oral administration. We attempted to confirm the effects of administration of intravenous alendronate, which is not inferior to oral administration, for osteoporotic patients in earlier research. 200 consecutive Japanese over 70 years-old postmenopausal women who visited the first author’s orthopedic clinic and had femoral neck or lumbar spine bone mineral density (BMD) values more than 2.5 SD lower than the reference values were randomly enrolled in this study. 100 subjects were recruited for administration of intravenous alendronates because of their poor adherence, no respond of treatment status, and gastrointestinal adverse effects. Furthermore, 10 of these subjects were excluded due to discontinuation, and a total of 90 subjects were eligible for the intravenous group. The remaining 50 patients received oral alendronate. The present study also showed no significant difference between intravenous and oral administration with respect to BMD, biochemical bone turnover markers, and the incidence of fractures. These results show that intravenous administration of alendronate is not inferior to oral alendronate for the treatment of osteoporosis. Therefore, intravenous administration of alendronate can be recommended if patients do not tolerate or adhere to oral bisphosphonates.

Alendronate does not prevent long bone fragility in an inactive rat model.

The lack of estrogen and inactivity are both important in the pathogenesis of osteoporosis in elderly women, and there have been no appropriate rodent studies to examine the effects of common bisphosphonates on these two components separately. We compared the efficacy of alendronate (ALN) on the long bones of aged female rats, which were sedentary, estrogen deficient, or both. The rats were either forced to remain in a sitting position or allowed to walk in standard cages with or without ALN administration. The 8-week experimental period began 5weeks after ovariectomy or sham surgery. Parameters of the hindlimb bones were determined by a three-point bending test, peripheral quantitative computed tomography, microfocus computed tomography, confocal laser Raman microspectroscopy, and dynamic histomorphometry. Regardless of ovariectomy, ALN was ineffective against the deterioration of breaking stress caused by sitting even though the trabecular bone mineral density was significantly higher in the sitting-ALN groups. Toughness was significantly deficient in the ovariectomy sitting-ALN group. This was in agreement with the bone geometry with a greater marrow space. Sitting also increased the mineral-to-matrix ratio and the carbonate-to-phosphate ratio, both indicative of aged bone. A greater loss of proteinaceous amide intensity compared with mineral intensity resulted in an increased mineral-to-matrix ratio in the presence of ALN. Sitting resulted in deficits in the quality and the geometry of cortical bone, resulting in fragility. The use of bisphosphonates, such as ALN, may provide a therapy best suited for osteoporotic individuals whose daily activity is not limited.

An osteonecrosis model induced by oral bisphosphonate in ovariectomised rats.

To develop a model of osteonecrosis using oral bisphosphonate in ovariectomy-induced osteoporotic rats. Thirty-six rats were subjected to ovariectomy or sham surgery. After 8 weeks, rats received oral alendronate (1.0 mg kg(-1) ) or saline once weekly for 4 weeks; then, serum C-telopeptide cross-linked collagen type I levels were measured to evaluate bone metabolism. Twelve rats from each group were injected with either lipopolysaccharide or saline into the bone marrow of the mandibles and femurs, and the areas of osteonecrosis were evaluated by histomorphometry. Serum C-telopeptide cross-linked collagen type I levels were significantly increased in the ovariectomy group (105.1 ± 2.1 ng ml(-1) ) compared with the sham group (78.9 ± 12.5 ng ml(-1) ); they were significantly reduced following oral alendronate administration in the ovariectomy group (91.0 ± 4.4 ng ml(-1) ). Following alendronate and lipopolysaccharide administration, extensive osteonecrosis was observed in the mandibles and femurs of ovariectomy (0.45 ± 0.08 mm(2) , 1.69 ± 0.72 mm(2) , respectively) and sham (1.12 ± 0.45 mm(2) , 1.84 ± 0.66 mm(2) , respectively) groups. Significantly wider osteonecrosis occurred in the mandibles of sham-operated rats than ovariectomy rats following alendronate or lipopolysaccharide treatment. We successfully developed a model of osteonecrosis in ovariectomised rats following oral bisphosphonate administration.

Protective Effects of Simvastatin Against Alendronate-Induced Gastric Mucosal Injury in Rats.

It has been reported that simvastatin, a statin commonly prescribed for its anti-inflammatory and antioxidant effects, has gastroprotective effects in indomethacin and ethanol-induced gastric ulcers. However, the effects of simvastatin on alendronate-induced gastric mucosal injury remain unexplored. This study investigated the use of simvastatin for the treatment of alendronate-induced gastric ulcers in rats. Female rats were pretreated with vehicle or simvastatin (20 and 60 mg/kg p.o.). After 1 h, the rats received alendronate (50 mg/kg p.o.). Simvastatin was administered once daily for 7 days, and from the fourth day of simvastatin treatment, alendronate was administered once daily for 4 days. On the final day of treatment, 4 h after alendronate administration, animals were euthanized, their stomachs were removed, and gastric damage was measured. Samples of the stomach were fixed in 10 % formalin immediately after their removal for subsequent histopathological assessment. Unfixed samples were weighed, frozen at -80 °C until assayed for glutathione (GSH), malondialdehyde (MDA), and cytokine levels and myeloperoxidase (MPO) activity. A third group was used to measure mucus and gastric secretion. Pretreatment with simvastatin prevented alendronate-induced macroscopic gastric damage and reduced the levels of MDA and GSH, TNF-α and IL-1β, MPO activity, and mucus levels, in the stomach. This study demonstrates the protective effects of simvastatin against alendronate-induced gastric ulceration. Maintenance of mucosal integrity, inhibition of neutrophil activity, and reduced oxidative stress associated with decreased gastric acidity may explain the gastroprotective effects of simvastatin.

Effect of alendronate on the mandible and long bones: an experimental study in vivo.

Bisphosphonates are anticatabolic agents that inhibit bone resorption and are widely used to treat osteoporosis and bone metastases in adults. They are also used in young patients with diseases like osteogenesis imperfecta or juvenile osteoporosis. Bone modeling/remodeling is elevated in growing subjects, and inhibition of osteoclastic activity has been shown to interfere with growth. Thus, our objective was to evaluate the effect of alendronate (ALN) on growing animals. Healthy male Wistar rats, aged 1 mo, received ALN or vehicle for 8 wk. Serum levels (calcemia, phosphatemia, and total alkaline phosphatase) were determined. Morphometric (rat: femur and tibia weight and length and hemimandible growth) and histomorphometric parameters (thickness of tibial epiphyseal cartilage and each cartilage zone, interradicular bone volume in the first lower molar, trabeculae volume, percentage of bone and cartilage, and osteoclast number in mandibular condyles) were assessed. ALN caused a significant decrease in femur and tibia length, tibial cartilage thickness, and longitudinal growth of hemimandibles. It increased interradicular bone volume and mandibular condyle trabeculae volume, increasing the percentage of cartilage and osteoclast number. These findings indicate that administration of ALN to growing animals alters the endochondral ossification process, and thus alters growth.

Dental implants treatment outcomes in patient under active therapy with alendronate: 3-year follow-up results of a multicenter prospective observational study.

To evaluate the 3-year clinical and radiographic data of fixed implant-supported dental prosthesis delivered to patients having taken alendronate 35-70mg weekly for at least 3years before implant placement. Forty consecutive patients treated with oral bisphosphonates and requiring an implant-supported restoration were recruited in two private centers between January 2008 and December 2011. Implants were inserted through minimally invasive approach under antibacterial and antibiotic treatment, 6months after alendronate administration stopping. After 4months of submerged healing, implants underwent prosthetic loading. Hygiene maintenance and clinical assessments were scheduled every 4months for 3years. Outcome measures were the following: implant and prosthetic success, survival rates, any observed clinical complications, marginal bone remodeling, probing pocket depth and bleeding-on-probing. At the end of the study, eight patients dropped out. The final sample size resulted in 32 consecutive partially or fully edentulous patients (32 females; mean age 64.6years) with 98 submerged implants. In only one patient, maxillary implant failed during healing period. No prosthesis failed during the entire follow-up, and no major complications were recorded. Implant and prostheses success resulted in an overall survival rate of 98, 98% and 100%, respectively. Three-year mean marginal bone loss was 1.35±0.21 (CI 95% 1.24-1.38). Successful soft tissue parameters were found around all implants. Oral bisphosphonate therapy did not appear to significantly affect implant survival and success in case of accurate treatment time selection, minimally invasive surgical approach and constant follow-up. Further prospective studies involving larger sample sizes and longer durations of follow-up are required to confirm these results.

Abstract P6-17-02: Inhibition of osteolytic tumor growth by 5-FdU-alendronate, a bisphosphonate conjugate that maintains bone formation: Implications for treatment of osteolytic bone lesions

Abstract Patients with breast cancer bone metastases suffer significant morbity from skeletal-related events but an effective agent that inhibits bone resorption while maintaining bone formation has not been identified. In this study we tested the therapeutic efficacy of a novel drug, 5-FdU-ale, a conjugate between the anti-metabolite 5-FdU and the bisphosphonate alendronate, in a mouse model of breast cancer bone metastases. Administration of 5-FdU-ale in vitro induces cell cycle arrest similar to treatment with unconjugated 5-FdU. In vivo, mice harboring bone lesions treated with 5-FdU-ale showed a reduction in tumor size not observed with administration of either Alendronate or 5-FdU. Since osteolysis mediated release of growth factors from bone contribute to tumor growth, we show 5-FdU-ale treatment significantly reduces bone resorption, although uniquely, the inhibition of osteoclast activity is not mediated through inhibition of prenylation of small GTPases. Furthermore, and in contrast to Alendronate, there is no concomitant decrease in bone formation activity, as determined by serum osteocaclin levels. This finding is supported by micro-CT analyses which reveal significantly higher bone volume and histologically, pockets of tumor cells are observed largely confined to regions of marrow space between endochondral and trabecular bone. Taken together, we conclude that 5-FdU-ale has potent anti-tumor efficacy in osteolytic bone lesions mediated uniquely through bone formation activity of osteoblasts and inhibition of bone resorption. The study identifies the important role of osteoblast in not only preventing the osteolytic metastatic phenotype but as a means of harnessing the therapeutic potential of bone formation to treat osteolytic lesions. Citation Format: Christian Schem, Rob J Tower, Philipp Kneissl, Anna C Rambow, Graeme M Campbell, Thorsten Heilmann, Anna Trauzold, Walter Jonat, Claus C Glüer, Sarah Schott, Sanjay Tiwari. Inhibition of osteolytic tumor growth by 5-FdU-alendronate, a bisphosphonate conjugate that maintains bone formation: Implications for treatment of osteolytic bone lesions [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-17-02.

Evaluation of the effects of LLLT on biomechanical properties of tibial diaphysis in two rat models of experimental osteoporosis by a three point bending test.

Osteoporosis (OP) is a disease which causes bone loss and fractures, leading to severe pain and deformity. This study has aimed to assess the effects of pulsed wave low-level laser therapy (PW LLLT) on cortical bone in two experimental models of OP in rats. There were four ovariectomized (OVX-d) groups and four dexamethasone-treated groups. The healthy group were considered for baseline evaluations. At 14weeks following ovariectomy, the OVX-d rats were further subdivided into the following: control rats with OP, OVX-d rats that received alendronate (1mg/kg), OVX-d rats treated with LLLT, and OVX-d rats treated with alendronate and LLLT. The remaining rats received dexamethasone for 5weeks and were divided into four groups: control, alendronate-treated rats (1mg/kg), laser-treated rats, and laser-treated rats with concomitant administration of alendronate. The rats received alendronate for 30days. LLLT (890nm, 80Hz, 0.972J/cm(2)) was performed on the tibias three times per week for 8weeks. After 8weeks, tibias were extracted and submitted to a three-point bending test. PW LLLT did not increase the biomechanical parameters of osteoporotic bones compared to controls and healthy rats. PW LLLT associated with alendronate treatment significantly increased stress high load in OVX-d rats compared to the healthy group. PW LLLT at the current study parameters failed to cause beneficial biomechanical effects in the examined osteoporotic cortical bones. PW LLLT associated with alendronate treatment produced a more remarkable effect on bone strength in the ovariectomized induced OP rat model.

Ultrastructural alterations of the inferior alveolar nerve in wistar rats after alendronate administration per os: hypothesis for the generation of the "numb chin syndrome"

Background: The neurological condition called ‘numb chin syndrome’, is a mental nerve neuropathy that is frequently associated with an underlying malignancy or infections. Bisphosphonate (BP) uptake has been recently identified as a new etiology for the syndrome. The mechanism that lies behind this neuropathy and the involvement of BPs have not been elucidated, yet. BPs can cause inhibition of endothelial cell proliferation, migration and adhesion, as well as impairment of capillary tubes formation. In humans, BPs result in reduction of vascularization in bone metabolic diseases, like Paget’s disease. We hypothesize that BPs, taken per os, are capable of producing degenerative changes to the inferior alveolar nerve that may cause a mental nerve neuropathy. Methods: In order to support our hypothesis we conducted an animal study, with Wistar rats, that was approved by the Bioethics Committee of our Institution. The animals were randomly allocated into two groups: Group A, the experimental group that consisted of 3 animals that were given Alendronate per os and Group B, the control group that also consisted of 3 animals, which were given normal saline. The duration was 13 weeks. The samples were observed under a Transmission Electron Microscope. Results: Degenerative changes were defined as: vacuolization of the myelin sheath, detachment of the axon, local thickening and/or disruption of the myelin sheath. Local myelin thickening and detachment of the axon was found in both groups. Myelin sheath disruption was only seen in the control group whereas vacuolization of the myelin sheath was more profound in the experimental group. Interestingly, myelin sheath thickness was reduced in the experimental group. Conclusions: Possible pathophysiological mechanisms causatively related to the histological alterations are: 1. alterations to the blood vessels of the nerve, 2. toxicity effects on Schwann and neuronal cells, or 3. changes to the innate or acquired immunity. The last may, probably, result from the presence of microbial films that cause cytokine production. The hypothesis provides scientific evidence for the presence of degenerative changes after BPs administration and helps in understanding of possible pathophysiological mechanisms.

Effects of the long‐term administration of alendronate on the mechanical properties of the basal bone and on osseointegration

To evaluate the effect of the long-term administration of alendronate on the mechanical properties of the basal bone and on osseointegration. One hundred and sixty female rats were randomly allocated into two equally sized groups: the control (CTL) group, which received the subcutaneous administration of saline solution, and the alendronate (ALD) group, which received the subcutaneous administration of alendronate (1mg/kg/week). After 120days of these therapies, one implant was placed in each rat tibia. Ten animals in each group were euthanized at 5, 10, 15, 20, 25, 30, 45, or 60days after surgery. The tibias with implants evaluated regarding the removal torque, bone-implant contact (BIC), the bone area fraction occupancy (BAFO), and Ca/P ratio. The femurs were evaluated regarding bone mineral density (BMD) and using mechanical tests to evaluate the maximal force of fracture, stiffness, and tenacity. The ALD group presented statistically significant higher BMD (all periods except 15days), maximal force of fracture (at 20, 30, and 45days), tenacity (at 10, 20, 30, and 45days), stiffness (45days), removal torque (at 20, 25 and 30 days), BIC (at 20 and 60days), and BAFO (at 20, 30, and 45days) than the CTL group. No differences were found between the groups regarding the Ca/P ratio. Previous long-term therapy with alendronate caused an increase in the BMD, maximal force of fracture of the bone without changing the inorganic composition and elastic deformability of this tissue. Furthermore, the ALD therapy enhanced osseointegration.

THU0386 Seven Cases of Multicentric Reticulohistiocytosis Treated with Intravenous Administration of Alendronate

BackgroundMulticentric reticulohistiocytosis (MR) is a rare systemic disorder characterized by cutaneous papulonodular lesions and severe destructive arthritis. Histologic analysis of cutaneous and synovial lesions discloses infiltration by multinucleated foreign body-type...

I–3 Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)

Objective: We proposed a site-specific mechanism of mouse mandibular bone remodeling in which osteoblasts express RANKL and BCL-2 only when mechanically loaded. Gene expression is regulated by α5β1 integrin, as a cellular defense mechanism against exposure to oral bacteria that would otherwise induce bone resorption through production of inflammatory cytokines (Exp Cell Res 2011). We hypothesize that loss of occlusal force caused by tooth extraction and bacterial infection increases the risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). If mechanical stimulation is required to sustain remodeling and prevent osteoblast apoptosis, then tooth extraction will induce BRONJ. The aim of this study is to induce BRONJ in a rat model through tooth extraction and to test whether LIPUS exposure can prevent BRONJ. Methods: To evaluate the effect of LIPUS exposure, we removed maxillary first molars from female ovariectomized rats following 4 weeks of subcutaneous alendronate administration. In addition, Porphyromonas gingivalis was topically applied to the molar during the last 3 weeks. LIPUS was applied extrabuccally to the extraction socket 5 times a week for 4 weeks in LIPUS-treated cells and was not applied in non-LIPUS-treated cells. Results and Discussion: In rats given alendronate and not LIPUS, delayed healing of the epithelium and alveolar bone was observed in the socket. In addition, there were involucrum sequestra in which the epithelial invaginations contained pieces of necrotic bone. In rats given alendronate with LIPUS, wounds healed normally, as judged by the restored activity of TRAP and ALP. In this rat model, we showed that tooth removal resulted in BRONJ-like pathology. LIPUS exposure can prevent BRONJ, perhaps by providing an alternative mechanical stimulus which inhibited inflammation. LIPUS normalized the healing process in the wound and the alveolar bone.

MP27-09 OBESE PATIENTS TAKING POTASSIUM CITRATE ARE LESS PRONE TO CALCIUM PHOSPHATE CALCULI THAN NON-OBESE

INTRODUCTION AND OBJECTIVES: Osteoporosis, which is characterized by a reduction in bone mineral density (BMD), is frequently detected in postmenopausal women as well as in men. Reduced BMD has been reported in patients with urolithiasis associated with hypercalciuria or normocalciuria. Bisphosphonates potently inhibit bone resorption and are used in the management of osteoporosis. We have reported that bisphosphonate prevents the recurrence of urinary stones in postmenopausal women. In this study, we investigated the ability of bisphosphonate to prevent the recurrence of urolithiasis in men with osteoporosis. METHODS: We studied 25 men aged <70 years (55.4 9.4 years) who were diagnosed with osteoporosis without hypercalciuria. Patients using steroids or anti-osteoporosis drugs were excluded. The patients’ stones were composed of calcium oxalate (CaOx) (n 1⁄4 17) or CaOx + calcium phosphate (CaP; n 1⁄4 8). We analyzed serum and 24hour urine specimens collected before and 1 month, 3 months, and 12 months after initiation of oral administration (5 mg/day or 35 mg/week) of alendronate (ALN), a new-generation bisphosphonate compound. The indices of the ionic activity products of CaOx (AP(CaOx)) and CaP (AP(CaP)) were estimated using the Tiselius method. Eleven of the 12 patients continued treatment for 24 months. We analyzed the ability of ALN to prevent the recurrence of urolithiasis by comparing the results with those of control subjects with osteoporosis (n 1⁄4 18, 56.2 9.7 years) who were treated for urolithiasis without ALN administration. RESULTS: ALN rapidly and significantly reduced the excretion of urinary calcium (162 75 [before] to 116 67 [3 months] and 118 75 [12 months] mg/day; p < 0.05) and the AP(CaOx) index (1.55 0.67 [before] to 0.89 0.79 [3 months] and 0.90 0.77 [12 months]; p < 0.05). The AP(CaP) index tended to decrease (1.27 0.75 [before] to 0.96 1.20 [3 months] and 0.95 1.24 [12 months]) as well. The urinary oxalate and phosphate levels showed no significant change. The incidence of urolithiasis (episodes/year) was significantly lower in patients treated with ALN than in those who were not (0.083 and 0.250, respectively; p < 0.05). CONCLUSIONS: ALN appears not only to improve BMD and alleviate osteoporosis but also to reduce the risk of calcium stone formation in men with osteoporosis. Bisphosphonate is believed to reduce the urinary excretion of calcium by improving bone metabolism and to prevent urolithiasis directly by preventing CaOx crystallization.

MP27-08 STONE PREVENTION WITH MEDICAL MANAGEMENT: FACTORS AFFECTING COMPLIANCE AND ADHERENCE

INTRODUCTION AND OBJECTIVES: Osteoporosis, which is characterized by a reduction in bone mineral density (BMD), is frequently detected in postmenopausal women as well as in men. Reduced BMD has been reported in patients with urolithiasis associated with hypercalciuria or normocalciuria. Bisphosphonates potently inhibit bone resorption and are used in the management of osteoporosis. We have reported that bisphosphonate prevents the recurrence of urinary stones in postmenopausal women. In this study, we investigated the ability of bisphosphonate to prevent the recurrence of urolithiasis in men with osteoporosis. METHODS: We studied 25 men aged <70 years (55.4 9.4 years) who were diagnosed with osteoporosis without hypercalciuria. Patients using steroids or anti-osteoporosis drugs were excluded. The patients’ stones were composed of calcium oxalate (CaOx) (n 1⁄4 17) or CaOx + calcium phosphate (CaP; n 1⁄4 8). We analyzed serum and 24hour urine specimens collected before and 1 month, 3 months, and 12 months after initiation of oral administration (5 mg/day or 35 mg/week) of alendronate (ALN), a new-generation bisphosphonate compound. The indices of the ionic activity products of CaOx (AP(CaOx)) and CaP (AP(CaP)) were estimated using the Tiselius method. Eleven of the 12 patients continued treatment for 24 months. We analyzed the ability of ALN to prevent the recurrence of urolithiasis by comparing the results with those of control subjects with osteoporosis (n 1⁄4 18, 56.2 9.7 years) who were treated for urolithiasis without ALN administration. RESULTS: ALN rapidly and significantly reduced the excretion of urinary calcium (162 75 [before] to 116 67 [3 months] and 118 75 [12 months] mg/day; p < 0.05) and the AP(CaOx) index (1.55 0.67 [before] to 0.89 0.79 [3 months] and 0.90 0.77 [12 months]; p < 0.05). The AP(CaP) index tended to decrease (1.27 0.75 [before] to 0.96 1.20 [3 months] and 0.95 1.24 [12 months]) as well. The urinary oxalate and phosphate levels showed no significant change. The incidence of urolithiasis (episodes/year) was significantly lower in patients treated with ALN than in those who were not (0.083 and 0.250, respectively; p < 0.05). CONCLUSIONS: ALN appears not only to improve BMD and alleviate osteoporosis but also to reduce the risk of calcium stone formation in men with osteoporosis. Bisphosphonate is believed to reduce the urinary excretion of calcium by improving bone metabolism and to prevent urolithiasis directly by preventing CaOx crystallization.

Low-energy femoral shaft fractures after long-term alendronate therapy: report of seven cases

There is increasing evidence suggesting a high incidence of low-energy fractures of the diaphysis or the proximal femur in patients receiving bisphosphonates for a long time. Bisphosphonate-related femoral fractures occur after low-energy trauma and have a typical simple transverse or oblique radiographic pattern, with focal or generalized increased cortical thickness, cortical beaking, and medial spiking. This article presents six female patients who experienced seven transverse femoral diaphysis and subtrochanteric fractures with cortical thickening and beaking; all patients had alendronate treatment for 4-10 years (average, 9 years) before their fracture. The typical radiographic findings, long-term administration of alendronate, low-energy mechanism of fracture, and related literature support the fact that the fractures in the patients presented in this series should be related to alendronate treatment. Until definite evidence is available, alendronate treatment in patients with osteoporosis is not now prohibited by the healthcare authorities, probably because its beneficial influence outweighs the adverse effects. However, this adverse effect deserves attention of medical practitioners; physicians should be alert on alendronate's possible suppressive effect on bone turnover, which in turn may be responsible for the occurrence of femoral fractures.