Doses Of Alendronate Research Articles

Osteolytic Bone Loss and Skeletal Deformities in a Mouse Model for Early-Onset Paget's Disease of Bone with PFN1 Mutation Are Treatable by Alendronate.

A novel osteolytic disorder due to PFN1 mutation was discovered recently as early-onset Paget's disease of bone (PDB). Bone loss and pain in adult PDB patients have been treated using bisphosphonates. However, therapeutic strategies for this specific disorder have not been established. Here, we evaluated the efficiency of alendronate (ALN) on a mutant mouse line, recapitulating this disorder. Five-week-old conditional osteoclast-specific Pfn1-deficient mice (Pfn1-cKOOCL) and control littermates (33 females and 22 males) were injected with ALN (0.1 mg/kg) or vehicle twice weekly until 8 weeks of age. After euthanizing, bone histomorphometric parameters and skeletal deformities were analyzed using 3D μCT images and histological sections. Three weeks of ALN administration significantly improved bone mass at the distal femur, L3 vertebra, and nose in Pfn1-cKOOCL mice. Histologically increased osteoclasts with expanded distribution in the distal femur were normalized in these mice. Geometric bone shape analysis revealed a partial recovery from the distal femur deformity. A therapeutic dose of ALN from 5 to 8 weeks of age significantly improved systemic bone loss in Pfn1-cKOOCL mice and femoral bone deformity. Our study suggests that preventive treatment of bony deformity in early-onset PDB is feasible.

Evaluation of the effects of melatonin on the post-extraction sockets of wistar rats exposed to a therapeutic dose of alendronate

ObjectivesThe objective was to evaluate the effects of melatonin administration on the post-extraction alveoli of rats exposed to alendronate. Materials and methodsThis was a pre-clinical cohort study of adult male Wistar rats, conducted over a period of 5 months in an animal facility suitable for animal experiments.Rats in groups 1 and 2 received melatonin and vitamin D respectively per os at a rate of 1 mg/kg/week and 0.25 mg/kg twice a week for 4 weeks. Group 3 received saline subcutaneously. All rats received alendronate at a dose of 0.05 mg/kg twice/week for 8 weeks. Four weeks after drug administration, a dental extraction was performed along with blood sampling to determine serum levels of RANKL and OPG. At eight weeks, the rats were sacrificed and the jaw blocks were removed for CT and histological examination. ResultsOverall, three groups of 12 rats were formed. From the fourth to the eighth week, the frequency of stage 3 osteonecrotic lesions in the post-extraction sockets had increased in the control group from 8.33% to 66.6%. In the melatonin and vitamin D groups, the frequency of corresponding stage 3 osteonecrotic lesions increased from 0 to 17% and 0–8.33% respectively. ConclusionOral administration of melatonin prior to tooth extraction in alendronate-exposed rats reduces the risk of developing osteonecrotic jaw lesions.

Clinical, CT profile of wistar rats receiving therapeutic doses of alendronate alone and in combination with cyclophosphamide and dexamethasone

IntroductionThe exact pathogenesis of drug-induced osteonecrosis of the jaw is still unknown. The aim of this study is to develop a reliable rat model of alendronate-related osteonecrosis of the jaw and to determine the CT profile of bisphosphonate-induced osteonecrosis of the jaw. Materials and methods98 Wistar rats were divided into 4 groups. Rats in the test groups received, in addition to 0.05 mg/kg alendronic acid orally (twice a week for 8 consecutive weeks), 1 mg/kg/day subcutaneously of dexamethasone for 2 weeks and 150 mg/kg cyclophosphamide orally twice and once a week before and after dental avulsion. ResultsFrom week 4 to week 8 after drug administration, the frequency of stage 3 osteonecrotic lesions increased in the test groups from (G1 = 5 (18.5%); G2 = 11 (39.2%); G3 = 6 (21.4%)) to (G1 = 8 (32%); G2 = 12 (42.8%); G3 = 13 (46.4%)) respectively. However, healing was not impaired in the control group (p = 0.003).Scannographic analysis showed that the difference in bone mineral density was greater in rats exposed (G2 = 486.22 ± 94.76; G3 = 584.9 ± 42.47) to the drug combinations than in rats exposed (G1 = 421.61 ± 125.81) to alendronate alone. ConclusionBased on this study, the rat treated with alendronate in combination or not with dexamethasone and cyclophosphamide and dental extraction can be considered as a new, reliable and reproducible model to better understand the pathophysiology of osteonecrosis of the jaws in the context of osteoporosis and prostate cancer. Furthermore, bone mineral density has been shown to be an important diagnostic criterion.

Preventive treatment with alendronate of loss of bone mineral density in acute traumatic spinal cord injury. Randomized controlled clinical trial

Randomized controlled clinical trial of two parallel groups. Analyse the efficacy of primary prevention with alendronate on the loss of bone mass which occurs during the first year of traumatic SCI, measured by double-energy X-ray bone densitometry (DXA). National Hospital for Paraplegics (HNP), Toledo, Spain. We included 52 people admitted to the HNP with traumatic SCI Grade A and B on the ASIA Impairment Scale and less than 8 weeks of progression, which were randomized to one of the two treatment groups. Both groups received calcifediol and a calcium-enriched diet for 52 weeks. Only one group was administered alendronate 70 mg weekly. The dose of alendronate was adjusted according to changes in serum β-CTX. 52 Participants were randomized. Of the 26 assigned to each group, 4 patients were lost in the alendronate group and 3 in the control group. The random distribution of women was asymmetrical, so we analysed the effect of treatment on men. In the total left hip, the mean (SD) decrease in bone mass was -22.791% (10.768) in the control group compared to the mean (SD) decrease of -2.693% (6.283) in the same location in the alendronate group (p < 0.0001). No patient presented related adverse events. Alendronate administered for one year in the first 8 weeks after traumatic SCI decreases bone loss in the hip in men. This treatment is well tolerated.

Anti-osteoporosis Effect of Fisetin against Ovariectomy Induced Osteoporosis in Rats: In silico, in vitro and in vivo Activity.

Osteoporosis is a bone related disease that is characterised by bone loss that further increases the susceptibility to bone fractures and bone frailty due to disturbances in the micro-architecture of bone tissue. Fisetin (flavonoids) exhibited anti-inflammatory and antioxidative stress effects against various diseases. In this protocol, we make an effort to comfort the anti-osteoporosis effect of fisetin against ovariectomy (OVX) induced osteoporosis. A docking study of fisetin and alendronate on the estrogen (α and β) and vitamin D receptors was carried out. SaOS-2 (osteoblast like human) cells were used for the estimation of cell proliferation. The OVX induced OVX model was used and three doses of fisetin and alendronate was given to rats till 16 weeks. The hormone levels, bone turnover markers and biochemical parameters were estimated. Fisetin was docked into estrogen (α and β) and vitamin D receptors, resulting in stable complexes with lower binding scores. Fisetin significantly (p < 0.001) exhibited the induction of cell proliferation against the SaOS-2 cells. OVX induced osteoporosis rats exhibited a suppression of body weight and uterus index, after the Fisetin treatment. Fisetin treatment significantly (p < 0.001) improved the level of bone mineral content (BMC), bone mineral density (BMD) and biochemical parameters such as energy, maximum load, stiffness, young modules, maximum stress and reduced the level of 1,25(OH) 2 D3 and E 2 . Fisetin treatment significantly (p < 0.001) declined the level of phosphorus (P), calcium (Ca) and boosted the level of VitD. Fisetin treatment significantly (p < 0.001) reduced the malonaldehyde (MDA) level and enhanced the glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) level in the bone, intestine and hepatic tissue. Fisetin treatment suppressed the cytokines, RANKL/OPG ratio, receptor activator of nuclear factor-κB ligand (RANKL) and improved the level of osteoprotegerin (OPG). The findings suggest that fisetin could be a beneficial phytoconstituent for the treatment and prevention of postmenopausal osteoporotic complications.

Dose-dependent effects of pharmaceutical treatments on bone matrix properties in ovariectomized rats

As both anabolic and anti-catabolic osteoporosis drugs affect bone formation and resorption processes, they may contribute to bone's overall mechanical behavior by altering the quality of the bone matrix. We used an ovariectomized rat model and a novel fracture mechanics approach to investigate whether treatment with an anabolic (parathyroid hormone) or anti-catabolic (alendronate) osteoporosis drugs will alter the organic and mineral matrix components and consequently cortical bone fracture toughness. Ovariectomized (at 5 months age) rats were treated with either parathyroid hormone or alendronate at low and high doses for 6 months (age 6–12 months). Specifically, treatment groups included untreated ovariectomized controls (n = 9), high-dose alendronate (n = 10), low-dose alendronate (n = 9), high-dose parathyroid hormone (n = 10), and low-dose parathyroid hormone (n = 9). After euthanasia, cortical microbeams from the lateral quadrant were extracted, notched, and tested in 3-point bending to measure fracture toughness. Portions of the bone were used to measure changes in the 1) organic matrix through quantification of advanced glycation end-products (AGEs) and non-collagenous proteins, and 2) mineral matrix through assessment of mineral crystallinity. Compared to the ovariectomized group, rats treated with high doses of parathyroid hormone and alendronate had significantly increased cortical bone fracture toughness, which corresponded primarily to increased non-collagenous proteins while there was no change in AGEs. Additionally, low-dose PTH treatment increased matrix crystallinity and decreased AGE levels. In summary, ovariectomized rats treated with pharmaceutical drugs had increased non-collagenous matrix proteins and improved fracture toughness compared to controls. Further investigation is required for different doses and longer treatment periods.

The Effect of Alendronate on Osteoclastogenesis in Different Combinations of M-CSF and RANKL Growth Factors.

Bisphosphonates (BPs) are compounds resembling the pyrophosphate structure. BPs bind the mineral component of bones. During the bone resorption by osteoclasts, nitrogen-containing BPs are released and internalized, causing an inhibition of the mevalonate pathway. As a consequence, osteoclasts are unable to execute their function. Alendronate (ALN) is a bisphosphonate used to treat osteoporosis. Its administration could be associated with adverse effects. The purpose of this study is to evaluate four different ALN concentrations, ranging from 10−6 to 10−10 M, in the presence of different combinations of M-CSF and RANKL, to find out the effect of low ALN concentrations on osteoclastogenesis using rat and human peripheral blood mononuclear cells. The cytotoxic effect of ALN was evaluated based on metabolic activity and DNA concentration measurement. The alteration in osteoclastogenesis was assessed by the activity of carbonic anhydrase II (CA II), tartrate-resistant acid phosphatase staining, and actin ring formation. The ALN concentration of 10−6 M was cytotoxic. Low ALN concentrations of 10−8 and 10−10 M promoted proliferation, osteoclast-like cell formation, and CA II activity. The results indicated the induction of osteoclastogenesis with low ALN concentrations. However, when high doses of ALN were administered, their cytotoxic effect was demonstrated.

A randomized clinical trial on improving osteopenia in postmenopausal women after two years of preventive treatment with alendronate; a dose of 35 mg per week is more effective or a dose of 70 mg?

Introduction: Osteoporosis is the most common metabolic bone disease worldwide. In this disease, the bone mass decreases and as it progresses, the risk of fracture increases. Osteopenia occurs in the early stages of bone loss. Studies on the effective dose for treatment of osteopenia have been controversial. Objectives: In this randomized clinical trial, low doses versus high doses of alendronate were assessed during the osteopenic stage in postmenopausal women. Patients and Methods: The present study is a randomized clinical trial (RCT) that was performed on 152 postmenopausal women who were visited in Al-Zahra rheumatology clinic between 2016 and 2017. Patients were randomly divided into two groups. The first group with 35 and the second group with 70 mg of weekly alendronate were treated and followed for two years. Densitometry was performed on patients before and 2 years after the intervention, and the findings were compared. Results: The two groups were not significantly different in terms of age, gender, height, weight, body mass index (BMI) and menopause (P&gt;0.05). The bone mineral density (BMD) findings of both groups, including Fracture Risk Assessment Tool (FRAX) hip and vertebra/wrist, T-score hip and vertebrae, as well as Z-score hip and vertebrae, improved significantly after two years (P&lt;0.001), However, a comparison of the two therapeutic doses did not show a significant difference in terms of BMD improvements (P&gt;0.05). Conclusion: The findings of this study reported favorable results for the preventive treatment of alendronate in osteopenic women. In addition, due to gastrointestinal problems that are the main complaint of alendronate use, according to the results, a weekly dose of 35 mg can be recommended

Effect of Bisphosphonates on the Osteogenic Activity of Osteoprogenitor Cells Cultured on Titanium Surfaces.

This study investigated the effects of bisphosphonates, namely, alendronate and zoledronate, on the osteogenic activity of osteoprogenitor cells cultured on titanium surfaces at therapeutic doses in order to assess if altered osteoblastogenesis could compromise osseointegration and contribute to etiopathogenesis of painful disorders such as bisphosphonates-related osteonecrosis of the jaw (BRONJ) following implant placement. MC3T3-E1 Subclone 4 cells were utilized in this study. Therapeutic doses of alendronate and zoledronate were calculated based on reported peak plasma concentrations. The viability, proliferation, adhesion, and mineralization potential of cells was assessed using a LIVE/DEAD stain, alamarBlue assay, immunofluorescence microscopy, and Alizarin Red S staining, respectively. Therapeutic doses of zoledronate negatively affected cell viability, whereas therapeutic doses of alendronate significantly enhanced cell differentiation and the amount of bone formation compared with the control. The findings of this study may provide some insight into the pathogenesis of BRONJ development following implant placement in patients treated with zoledronate and may have promising implications toward improved wound healing and osseointegration in patients treated with alendronate.

T-Score as an Indicator of Fracture Risk During Treatment With Romosozumab or Alendronate in the ARCH Trial

ABSTRACTIn the Active‐Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) clinical trial (NCT01631214), 1 year of romosozumab followed by alendronate reduced the risk of vertebral and nonvertebral fractures compared to alendronate alone in women with prevalent fracture. We performed post hoc analyses of data from patients in ARCH (romosozumab, n = 1739; alendronate, n = 1726) who had a baseline BMD measurement and received at least one open‐label alendronate dose. We evaluated 1‐year mean BMD and corresponding T‐score changes; proportions of patients achieving T‐scores > −2.5 at the total hip (TH), femoral neck (FN), and lumbar spine (LS); and group differences in fracture rates after 12 months, while all participants were on alendronate. Subsequently, we investigated the relationship between T‐scores achieved at the TH, FN, and LS at 12 months and subsequent fracture incidence. At 1 year, mean change from baseline in TH BMD was 6.3% (T‐score change 0.31) with romosozumab versus 2.9% (T‐score change 0.15) with alendronate (p < .001). The proportion of patients with TH T‐score > −2.5 increased from 34% at baseline to 55% after 1 year of romosozumab and from 32% at baseline to 44% after 1 year of alendronate. Compared with patients receiving alendronate in year 1, those receiving romosozumab had a 75% reduction in new or worsening vertebral fracture (p < .001) in year 2, and a 19% reduction in nonvertebral fracture (p = .120) and 40% reduction in hip fracture (p = .041) during the open‐label period. TH and FN T‐scores achieved at month 12 were associated with subsequent nonvertebral and vertebral fracture rates and the relationships were independent of treatment received. LS T‐score at 12 months was associated with vertebral but not nonvertebral fracture risk. We conclude that 1 year of romosozumab leads to larger BMD gains versus alendronate, and that the T‐score achieved with either therapy is related to subsequent fracture risk. These data support the use of T‐score as a therapeutic target for patients with osteoporosis. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

History of alendronate.

Alendronate was synthesized in 1970s in a search for inhibitors of calcification. Istituto Gentili investigators identified it as a potent inhibitor of bone resorption and obtained a patent covering its use in the treatment of osteoporosis and other disorders of excessive bone resorption in the 1980s. Merck licensed alendronate in 1988 and its pharmaceutical chemists reformulated it as a sodium salt with good solubility in a tablet that reduced its potential for esophageal irritation. Clinical trials proved that it reduced bone turnover, increased BMD and reduced the risk of vertebral fractures in postmenopausal osteoporotic women. Merck sponsored a large clinical trials that won FDA approval for treatment of osteoporosis in postmenopausal women and showed that it reduced the risk of spine and hip fractures. Its approval in the US in 1995 spurred sales of bone densitometers and BMD testing to screen for low bone mineral density and identify osteoporosis. Bone mass measurement was supported by medical society guidelines and reimbursement by Medicare and other insurers in the USA. A 70 mg weekly instead of 10 mg daily dose of alendronate produced the same effect on BMD and biochemical markers of bone remodelling with greater convenience and reduced potential for upper GI adverse events. Consequently, by 2006, about 30 million prescriptions for alendronate were written annually in the U.S. for about 15% of postmenopausal women in the U.S. Thereafter, publicity about rare but concerning atypical femoral fractures (AFF) and osteonecrosis of the jaw (ONJ) along with the expiry of Merck's patent (in 2008) and cessation of their promotion of alendronate, and a decline in use of densitometry led to a steady slide in its use even among patients for whom the benefits of alendronate far outweigh its potential risks. Nevertheless, in 25years since its regulatory approval, alendronate has undoubtedly prevented millions of fractures world-wide.

MON-358 Hypercalcemia During Teriparatide Therapy

Background: Teriparatide (TPTD) is a recombinant PTH analog used as an anabolic agent in the treatment of osteoporosis that stimulates bone formation and activates bone remodeling. The most common side effects are nausea, vomiting, hypertension and dizziness. Transient hypercalcemia is a known adverse effect which is usually seen a few hours after administration and resolves within 16 hours. However, marked late hypercalcemia is a rare event and may be of concern in clinical practice. Clinical Cases: Case 1 is a 54-year-old man with a history of osteoporosis (lumbar spine T-score of -2.8), previously treated with bisphosphonates and who had been on a course of TPTD for about 6 months in but had not been consistent in taking the medication. Prior to subsequently restarting TPTD, his initial labs were notable for a normal Ca 9.3 mg/dl (8.5 - 10.1 mg/dl), vitamin D 25 OH 49 ng/ml (30.0 - 100.0 ng/ml) and PTH 41.3 pg/ml (8.7 - 77.1 pg/ml). Six months into the treatment, he was noted to have asymptomatic hypercalcemia of 11.2 mg/dl approximately 24 hrs after the last TPTD injection. A repeat calcium of 10.7 mg/dl was obtained while still on therapy with TPTD with normal levels of vitamin D 25 OH of 45 ng/ml. Case 2 is a 75-year-old woman with a history of osteopenia and severe scoliosis, who had been on a course of raloxifene and then preventive doses of alendronate previously. Prior to starting TPTD, her Ca levels were normal at 9.3 mg/dl, PTH was 24 pg/ml and vitamin D 25 OH was 33 ng/ml. However, six months into the treatment she was noted to have elevated Ca of 12.5 mg/dl (24 hrs after the last TPTD dose), with low levels of vitamin D 25 OH of 24.2 ng/ml. Ca levels returned to the baseline of 9.3 mg/dl when TPTD was held. Conclusion: Teriparatide has a long track record of safety and does have the rare side effect of hypercalcemia. 1-3% of patients may have mild hypercalcemia after administration. Intake of calcium and vitamin D should be monitored at the start of therapy given these concerns. Although almost never a cause of discontinuation of treatment in clinical practice, it is important to be aware of this side effect in patients who may be at risk of complications of hypercalcemia.

SAT-LB69 Severe Disabling Musculoskeletal Pain as a Side Effect of Bisphosphonates: A Case Report and Review of Literature

We report a case of a 57-year-old woman who developed severe musculoskeletal pain after taking one dose of Alendronate 70mg for treatment of osteoporosis. The pain was so debilitating that the patient was unable to sit up, stand, or move without assistance, and any kind of movement aggravated the pain.Key words: bisphosphonate, severe muscle pain, case report, osteoporosisMethodsA detailed case report is presented. A review of the current literature on the side effects of bisphosphonates was made for reference.ResultsDevelopment of severe, disabling musculoskeletal pain was noted after taking one dose of Alendronate 70 mg tablet. The pain was severe enough to hinder the patient from sitting or standing up, and any form of movement seemed to worsen the pain. Discontinuation of the drug, pain relievers and complete bed rest afforded slight relief of symptoms. Complete resolution of pain only occurred after 72 hours. Review of literature showed that muscle pain with intake of bisphosphonates occurred in a few patients, and were mostly found in case reports or case series. Other commonly associated side effects with bisphosphonate therapy were also briefly discussed.ConclusionThe case presented emphasizes that bisphosphonate therapy, although frequently used uneventfullyn, may still produce adverse effects in a few patients. A handful may present with severe debilitating muscle pain as seen in our patient. Literature review showed that another subset of patients may react differently and present with cardiac or ocular symptoms. What must be taken from this paper is the importance of patient education regarding these possible adverse events that although infrequent, may still happen. These unpleasant adverse effects may greatly affect compliance and ultimately have a bigger impact in the fight against osteoporosis.

Local application of alendronate controls bone formation and β‐tricalcium phosphate resorption induced by recombinant human bone morphogenetic protein‐2

This study examined the ability of local alendronate (ALN) administration to control β-tricalcium phosphate (β-TCP) resorption as well as the induction of bone formation by recombinant human bone morphogenetic protein-2 (rhBMP-2). A 15-mm critical-sized bone defect was created in the diaphysis of rabbit ulnae. Nine female rabbits (4 to 5 months-old) were divided into 3 groups. Group 1 (n = 6 ulnae) animals received implants consisting of β-TCP granules and 25 μg of rhBMP-2 in 6.5% collagen gel. Group 2 (6 ulnae) and Group 3 (6 ulnae) animals received the same implants, but with 10-6 M and 10-3 M ALN-treated TCP granules, respectively. Two weeks postsurgery, tartrate-resistant acid phosphatase-positive cell counts, new bone formation, and residual β-TCP were evaluated. This study showed that a high dose of ALN strongly reduced osteoclastic resorption of β-TCP induced by rhBMP-2, resulting in decreased bone formation. In contrast, a low dose of ALN slightly reduced the bone resorptive effect but increased bone formation. These results suggest that osteoclast-mediated resorption plays an important role in bone formation and a coupling-like phenomenon could occur in the β-TCP-implanted area, and that administration of a low dose of ALN may solve clinical bone resorptive problems induced by rhBMP-2.

Annals for Educators - 2 July 2019.

Annals for Educators - 2 July 2019.

Bone repair in craniofacial defects treated with different doses of alendronate: a histological, histomorphometric, and immunohistochemical study.

The objective of the study is to evaluate bone repair in rats treated with different alendronate doses. Sixty female rats ovariectomized were randomly divided in three groups: group C (control group), group A1 (ALN/1mg/kg), and A2 (ALN/ 3mg/kg). Each animal received subcutaneous applications of sodium alendronate at a dose correspondent to group A1 or A2 three times a week, while the control group received 0.9% saline solution. After 4weeks of application, a critical defect was created in the calvaria of animals of all groups. The defect was filled by particulate autogenous bone. The applications were maintained until euthanasia, which occurred 15 and 60days after the surgical procedure. The pieces were sent for histological, histomorphometric and immunohistochemical analysis. The data were submitted to statistical analysis with significance level of 0.05. The descriptive histological analysis demonstrated an increase in bone neoformation in both groups treated with alendronate when compared to the control group. The histomorphometric analysis showed an increase in the amount of neoformed bone in A1 and A2 groups when compared to group C, both at 15days (p = 0.0002) and at 60days (p = 0.001). In the immunohistochemical analysis, it was possible to observe a difference in immunolabeling just for Mmp2 at the time of 60days in A1 (p = 0.001) and A2 (p = 0.023) when compared to the control group. Systemic delivery of alendronate, regardless of the dose, increased the amount of bone neoformation. Prescription of sodium alendronate at 1mg/kg for improvement of bone neoformation in bone graft procedures.

GUT MICROBIOTA AND AUTISM

The purpose of this study was to comparatively investigate the posterolateral fusion rate in ovariectomized (OVX) rats using two new bone graft materials: strontium (Sr) substituted hydroxyapatite (HA) nanocrystals and alendronate (AL) functionalized HA nanocrystals. SrHA was synthesized in presence of different Sr concentrations (SrHA5; SrHA10) and HA-AL nanocrystals at increasing bisphosphonate (BP) content (HA-AL7; HA-AL28).A posterolateral spinal fusion model in twenty-five Sham operated and in twenty-five OVX female rats was used and materials were bilaterally implanted between transverse processes of lumbar vertebrae. Sham and OVX animals were divided in five groups depending on the material: HA, SrHA5, SrHA10, HA-AL7 and HA-AL28. The assessment of bone fusion was carried out by μCT, histology and histomorphometry.Some gaps between the transverse processes were observed by μCT in OVXHA group, while they were not present in all the other groups. These results were consistent with the histomorphometrical analyses showing that in OVX animals SrHA and HA-AL materials displayed significantly higher BV/TV and Tb.Th and significantly lower Tb.N and Tb.Sp in comparison with HA alone.Results of this study suggest that in spinal fusion the incorporation of bioactive ions or drugs as Sr and AL improves the biological performance of HA representing a promising strategy especially in osteoporosis patients with high risks of spinal fusion failure. Results also suggest the existence of a Sr and AL dose response effect and that HA containing the highest AL dose could be the candidate biomaterial for spinal fusion in osteoporotic subjects.

Antiresorptive properties of strontium substituted and alendronate functionalized hydroxyapatite nanocrystals in an ovariectomized rat spinal arthrodesis model

PurposeThe purpose of this study was to comparatively investigate the posterolateral fusion rate in ovariectomized (OVX) rats using two new bone graft materials: strontium (Sr) substituted hydroxyapatite (HA) nanocrystals and alendronate (AL) functionalized HA nanocrystals. SrHA was synthesized in presence of different Sr concentrations (SrHA5; SrHA10) and HA-AL nanocrystals at increasing bisphosphonate (BP) content (HA-AL7; HA-AL28). MethodsA posterolateral spinal fusion model in twenty-five Sham operated and in twenty-five OVX female rats was used and materials were bilaterally implanted between transverse processes of lumbar vertebrae. Sham and OVX animals were divided in five groups depending on the material: HA, SrHA5, SrHA10, HA-AL7 and HA-AL28. The assessment of bone fusion was carried out by μCT, histology and histomorphometry. ResultsSome gaps between the transverse processes were observed by μCT in OVXHA group, while they were not present in all the other groups. These results were consistent with the histomorphometrical analyses showing that in OVX animals SrHA and HA-AL materials displayed significantly higher BV/TV and Tb.Th and significantly lower Tb.N and Tb.Sp in comparison with HA alone. ConclusionsResults of this study suggest that in spinal fusion the incorporation of bioactive ions or drugs as Sr and AL improves the biological performance of HA representing a promising strategy especially in osteoporosis patients with high risks of spinal fusion failure. Results also suggest the existence of a Sr and AL dose response effect and that HA containing the highest AL dose could be the candidate biomaterial for spinal fusion in osteoporotic subjects.

Would Be Prophylactic Administrations of Low Concentration of Alendronate an Alternative for Improving the Craniofacial Bone Repair? A Preliminary Study Focused in the Period of Cellular Differentiation and Tissue Organization.

Alendronate (ALN) is a nitrogen-bisphosphonate that may induce an anabolic effect on craniofacial bone repair when administrated in low doses. Based on this premise, this study analyzed the influence of prophylactic low doses of ALN on bone healing in defects created in rabbit mandible. A 5 × 2-mm diameter deep defect was created in the calvaria of 28 rabbits. Fourteen of these rabbits received previously 50 μg/kg of 1% sodium ALN for 4 weeks, while the other rabbits received only 0.9% physiological saline solution (control). Animals were euthanized at 15 and 60 days postsurgery (n = 7), and the data were analyzed using histomorphometry and immunohistochemistry using the anti-CD34, bone morphogenetic protein -2 (BMP-2), and transforming growth factor (TGF)-β1 antibodies. On the 15th day postsurgery, the specimens that received previous treatment with ALN demonstrated large vascular lumen and intense positivity to CD34 either concentrated in endothelium or cells spread among the reparative tissue. These results coincided with intense positivity for BMP-2+ cells and TGF-β1 that was concentrated in both cells and perivascular area. In contrast, the control group revealed scarce cells that exhibited CD34, BMP-2+, and the TGF-β1 was restricted for perivascular area on well-formed granulation tissue. These patterns of immunohistochemical result, especially found on the 15th day of analysis, seem to be responsible for the development of larger quantities of bone matrix in the specimens that receive ALN on the 60th day postsurgery. These preliminary results showed that the prophylactic administration of low doses of ALN might be an alternative to craniofacial bone craniofacial bone repair because it increases the immunopositivity for TGF-β1 and consequently improves the CD34+ and BMP-2+ cells on reparative sites.

Effects of combination treatment with alendronate and raloxifene on skeletal properties in a beagle dog model.

A growing number of studies have investigated combination treatment as an approach to treat bone disease. The goal of this study was to investigate the combination of alendronate and raloxifene with a particular focus on mechanical properties. To achieve this goal we utilized a large animal model, the beagle dog, used previously by our laboratory to study both alendronate and raloxifene monotherapies. Forty-eight skeletally mature female beagles (1–2 years old) received daily oral treatment: saline vehicle (VEH), alendronate (ALN), raloxifene (RAL) or both ALN and RAL. After 6 and 12 months of treatment, all animals underwent assessment of bone material properties using in vivo reference point indentation (RPI) and skeletal hydration using ultra-short echo magnetic resonance imaging (UTE-MRI). End point measures include imaging, histomorphometry, and mechanical properties. Bone formation rate was significantly lower in iliac crest trabecular bone of animals treated with ALN (-71%) and ALN+RAL (-81%) compared to VEH. In vivo assessment of properties by RPI yielded minimal differences between groups while UTE-MRI showed a RAL and RAL+ALN treatment regimens resulted in significantly higher bound water compared to VEH (+23 and +18%, respectively). There was no significant difference among groups for DXA- or CT-based measures lumbar vertebra, or femoral diaphysis. Ribs of RAL-treated animals were smaller and less dense compared to VEH and although mechanical properties were lower the material-level properties were equivalent to normal. In conclusion, we present a suite of data in a beagle dog model treated for one year with clinically-relevant doses of alendronate and raloxifene monotherapies or combination treatment with both agents. Despite the expected effects on bone remodeling, our study did not find the expected benefit of ALN to BMD or structural mechanical properties, and thus the viability of the combination therapy remains unclear.