Effects of the combination treatment of raloxifene and alendronate on the biomechanical properties of vertebral bone

Raloxifene (RAL) and alendronate (ALN) improve the biomechanical properties of bone by different mechanisms. The goal here was to investigate the effects of combination treatment of RAL and ALN on the biomechanical properties of vertebral bone. Six‐month‐old Sprague‐Dawley rats (n = 80) were randomized into five experimental groups (sham, OVX, OVX + RAL, OVX + ALN, and OVX + RAL + ALN; n = 16/group). Following euthanization, structural and derived material biomechanical properties of vertebral bodies were assessed. Density and dynamic histomorphometric measurements were made on cancellous bone. The results demonstrate that the structural biomechanical properties of vertebral bone are improved with the combination treatment. Stiffness and ultimate load of the OVX + RAL and OVX + ALN groups were significantly lower than those of sham animals, but the combination treatment with RAL + ALN was not significantly different from sham. Furthermore, the OVX + RAL + ALN group was the only agent‐treated group in which the ultimate load was significantly higher than that in OVX animals (p < .05). Cancellous bone fractional volume (BV/TV_canc) and bone mineral density (aBMD) also were improved with the combination treatment. BV/TV_canc of the OVX + RAL + ALN group was 6.7% and 8.7% greater than that of the OVX + RAL (p < .05) and OVX + ALN (p < .05) groups, respectively. Areal BMD of the OVX + RAL or OVX + ALN groups was not significantly different from that in OVX animals, but the value in animals undergoing combination treatment was significantly higher than that in OVX or OVX + RAL animals alone and not significantly different from that in sham‐operated animals. Turnover rates of both the RAL + ALN and ALN alone groups were lower than in the RAL‐treated alone group (p < .05). We conclude that the combination treatment of raloxifene and alendronate has beneficial effects on bone volume, resulting in improvement in the structural properties of vertebral bone. © 2011 American Society for Bone and Mineral Research.     

Cathepsin K inhibitors prevent bone loss in estrogen‐deficient rabbits

Two cathepsin K inhibitors (CatKIs) were compared with alendronate (ALN) for their effects on bone resorption and formation in ovariectomized (OVX) rabbits. The OVX model was validated by demonstrating significant loss (9.8% to 12.8%) in lumbar vertebral bone mineral density (LV BMD) in rabbits at 13‐weeks after surgery, which was prevented by estrogen or ALN. A potent CatKI, L‐006235 (L‐235), dosed at 10 mg/kg per day for 27 weeks, significantly decreased LV BMD loss (p < .01) versus OVX‐vehicle control. ALN reduced spine cancellous mineralizing surface by 70%, whereas L‐235 had no effect. Similarly, endocortical bone‐formation rate and the number of double‐labeled Haversian canals in the femoral diaphysis were not affected by L‐235. To confirm the sparing effects of CatKI on bone formation, odanacatib (ODN) was dosed in food to achieve steady‐state exposures of 4 or 9 µM/day in OVX rabbits for 27 weeks. ODN at both doses prevented LV BMD loss (p < .05 and p < .001, respectively) versus OVX‐vehicle control to levels comparable with sham or ALN. ODN also dose‐dependently increased BMD at the proximal femur, femoral neck, and trochanter. Similar to L‐235, ODN did not reduce bone formation at any bone sites studied. The positive and highly correlative relationship of peak load to bone mineral content in the central femur and spine suggested that ODN treatment preserved normal biomechanical properties of relevant skeletal sites. Although CatKIs had similar efficacy to ALN in preventing bone loss in adult OVX rabbits, this novel class of antiresorptives differs from ALN by sparing bone formation, potentially via uncoupling bone formation from resorption. © 2011 American Society for Bone and Mineral Research.     

Antiresorptives overlapping ongoing teriparatide treatment result in additional increases in bone mineral density

During teriparatide (TPTD) treatment, high levels of bone formation are accompanied by an increase in bone resorption. The aim of this work was to test if coadministration of raloxifene (RAL) or alendronate (ALN) following 9 months of ongoing TPTD therapy would reopen the anabolic window, thereby exerting additional benefit on bone mineral density (BMD). Postmenopausal women (n = 125) with severe osteoporosis on TPTD treatment for 9 months were randomized into three open‐label groups for a further 9 months: ALN (70 mg/week) in addition to TPTD; RAL (60 mg/d) in addition to TPTD; or no medication in addition to TPTD. Amino‐terminal propeptide of type I procollagen (P1NP) and cross‐linked C‐telopeptide (CTX), and areal and volumetric BMD at the lumbar spine and hip were assessed. During the combination period, P1NP concentrations did not change on TPTD monotherapy (693% ± 371%, p < 0.0001) and decreased in the ALN (360% ± 153%, p < 0.0001) and RAL (482% ± 243%, p < 0.0001) combination groups; whereas CTX did not change on TPTD monotherapy (283% ± 215%, p < 0.0001), decreased to the starting level in the ALN combination group (17% ± 72%, p = 0.39), and remained elevated in the RAL combination group (179% ± 341%, p < 0.0001). The increase in lumbar spine BMD was 5% ± 6.3% in the ALN and 6% ± 5.2% in the RAL combination groups compared with 2.8% ± 9.3% in the TPTD monotherapy group (p = 0.085 and p = 0.033, respectively). The increase of trabecular lumbar spine BMD for both the ALN and RAL combination groups was superior to TPTD monotherapy. Total hip BMD changes were 4% ± 5.3% for the ALN combination group and 1.4% ± 5.1% for the TPTD monotherapy (p = 0.032), and 1.4% ± 3.4% (p = 0.02) for the RAL combination group. With the exception of no differences in the trabecular compartment of femoral neck, volumetric BMD changes in the ALN combination group for all other comparisons were significantly superior to the two other groups. Our data suggest that ALN when added to TPTD 9 months after initiation of TPTD monotherapy results in a more robust increase in BMD, probably due to a reopening of the anabolic window. The clinical relevance of the BMD increase is unknown. © 2013 American Society for Bone and Mineral Research     

Overlapping and Continued Alendronate or Raloxifene Administration in Patients on Teriparatide: Effects on Areal and Volumetric Bone Mineral Density—The CONFORS Study

Nine month teriparatide (TPTD) monotherapy followed by co‐administration of raloxifene (RAL) or alendronate (ALN) for another nine 9 months resulted in incremental bone mineral density (BMD) increase. The aim of this study was to investigate the effects of continued antiresorptive treatments for 12 months in the extension phase. Postmenopausal women (n = 125) with severe osteoporosis on ongoing TPTD treatment for 9 months were randomized into three open‐label groups for another 9 months: ALN (70 mg/week, n = 41), RAL (60 mg/d, n = 37) in addition to TPTD or no additional medication (n = 47) except Ca and vitamin D. After discontinuation of TPTD the respective antiresorptives were continued for a further 12 months, while patients in the TPTD monotherapy group received Ca and vitamin D. Amino‐terminal propeptide of type I procollagen (P1NP) and cross‐linked C‐telopeptide (CTX), areal and volumetric BMD at the lumbar spine (LS) and hip were assessed. ALN resulted in continued BMD increase in LS (4.3 ± 1.5%; mean ± SD), femoral neck (4.2 ± 1.6%) and total hip (4 ± 1.6%; p < 0.001 for all), while RAL was only effective at the LS (2.4 ± 1.7%, p < 0.001) but no changes at the femoral neck (0.4 ± 1.4%) or total hip (?0.8 ± 1.5%) were observed. Cortical bone only increased in the ALN group (femoral neck 6.7 ± 2.7% and ?1.3 ± 2.5%; total hip 13.8 ± 2.9% and ?2.3 ± 2.5% for ALN and RAL, p < 0.001 for all; respectively). Analyzing the entire 30 months of therapy, the ALN group revealed the largest BMD increase in all regions. Our results suggest that the addition of ALN to ongoing TPTD and continuing ALN after TPTD was stopped may be beneficial for patients in terms of areal and volumetric BMD increase. Further research is warranted to determine the optimal timing of the initiation of the combination treatment, the respective antiresorptive medication and the potential benefit of this BMD increase regarding fracture prevention. © 2014 American Society for Bone and Mineral Research     

Effects of alendronate on bone mineral density and bone metabolic markers in patients with liver transplantation

Introduction The purpose of this study was to evaluate the effects of alendronate (ALN) on bone mineral density (BMD) and bone turnover markers in patients with orthotopic liver transplantation (OLT). Methods In the prospective, controlled, open study with 24 months of follow-up, 98 patients with OLT were randomised to receive ALN 70 mg weekly or no ALN; calcium (Ca) 1,000 mg daily and 0.5 mcg calcitriol daily were provided to all patients. Lumbar spine (LS) and hip BMDs were measured at 6-month intervals by dual-energy X-ray absorptiometry (DEXA). Spinal radiographs were obtained to assess vertebral fractures. Additionally, bone turnover markers, serum parathyroid hormone (PTH) and biochemical parameters were determined every 3 months. Results Compared with the control group, the ALN group showed significant increases in BMD of the LS (5.1±3.9% vs 0.4±4.2%, p<0.05 at 12 months, 8.9±5.7% vs 1.4±4.9%, p<0.05 at 24 months), femoral neck (4.3±3.8% vs −1.1±3.1%, p<0.05 at 12 months, 8.7±4.8% vs 0.6±4.5%, p<0.05 at 24 months) and total femur (3.6±3.8% vs −0.6±4.0%, p<0.05 at 12 months, 6.2±3.8% vs 0.3±4.6%, p<0.05 at 24 months). In the ALN group, osteocalcin and urinary deoxypyridinoline (DPD) decreased significantly at the sixth month, with no further change, by −35.6% and −63.0%, on average, respectively (p<0.05). In the control group, a significant increase in biochemical markers of bone turnover was observed in comparison to baseline values (p<0.05). PTH increased within reference levels without a difference between groups. Two nonvertebral fractures (4.2%) and nine vertebral fractures (18.8%) in the control group and three vertebral fractures (6.8%) in the ALN group occurred during the follow-up. The weekly ALN was well tolerated, and no severe side effects occurred. Conclusion This is the first randomised study including a control group to demonstrate that weekly ALN was able to significantly increase BMD in patients with OLT when compared with Ca and calcitriol alone. However, ALN did not appear to offer protection against fractures. This study was awarded the “Novartis Young Investigator Award” at the Second Joint Meeting of the European Calcified Tissue Society and the International Bone and Mineral Society, Geneva, 25–29 June 2005.     

Prolonged Treatments With Antiresorptive Agents and PTH Have Different Effects on Bone Strength and the Degree of Mineralization in Old Estrogen‐Deficient Osteoporotic Rats

Current approved medical treatments for osteoporosis reduce fracture risk to a greater degree than predicted from change in BMD in women with postmenopausal osteoporosis. We hypothesize that bone active agents improve bone strength in osteoporotic bone by altering different material properties of the bone. Eighteen‐month‐old female Fischer rats were ovariectomized (OVX) or sham‐operated and left untreated for 60 days to induce osteopenia before they were treated with single doses of either risedronate (500 μg/kg, IV), zoledronic acid (100 μg/kg, IV), raloxifene (2 mg/kg, PO, three times per week), hPTH(1–34) (25 μg/kg, SC, three times per week), or vehicle (NS; 1 ml/kg, three times per week). Groups of animals were killed after days 60 and 180 of treatment, and either the proximal tibial metaphysis or lumbar vertebral body were studied. Bone volume and architecture were assessed by μCT and histomorphometry. Measurements of bone quality included the degree of bone mineralization (DBM), localized elastic modulus, bone turnover by histomorphometry, compression testing of the LVB, and three‐point bending testing of the femur. The trabecular bone volume, DBM, elastic modulus, and compressive bone strength were all significantly lower at day 60 post‐OVX (pretreatment, day 0 study) than at baseline. After 60 days of all of the bone active treatments, bone mass and material measurements agent were restored. However, after 180 days of treatment, the OVX + PTH group further increased BV/TV (+30% from day 60, p < 0.05 within group and between groups). In addition, after 180 days of treatment, there was more highly mineralized cortical and trabecular bone and increased cortical bone size and whole bone strength in OVX + PTH compared with other OVX + antiresorptives. Treatment of estrogen‐deficient aged rats with either antiresorptive agents or PTH rapidly improved many aspects of bone quality including microarchitecture, bone mineralization, turnover, and bone strength. However, prolonged treatment for 180 days with PTH resulted in additional gains in bone quality and bone strength, suggesting that the maximal gains in bone strength in cortical and trabecular bone sites may require a longer treatment period with PTH.     

Maintenance of bone mineral density of femoral cortex in ovariectomized rats after withdrawal of concurrent administration of human parathyroid hormone (1–34) and incardronate disodium (YM175)

The aim of this study was to evaluate the potential use of a combination of human parathyroid hormone (1–34) [hPTH(1–34)] and bisphosphonate (incadronate disodium cycloheptylaminomethylenedisphosphonate monohydrate, YM175) as a therapy for osteoporosis. We examined the effects of concurrent administration of PTH and YM175 or single administration and the persistence of their therapeutic effect after withdrawal on bone mineral density (BMD) of the femur in ovariectomized rats with established osteopenia. One hundred and two 11-week-old Sprague-Dawley rats were divided into sham operation and ovariectomy (OVX) groups. OVX rats were untreated for the first 4 weeks post ovariectomy to allow for the development of moderate ovariectomy to allow for the development of moderate osteopenia. These animals were then subjected to various treatment regimens with either PTH, YM175, or both for 4 weeks. The animals were then killed at 4 or 12 weeks, after withdrawal of the treatment and the bone mineral density (BMD) of distal, middle, proximal part, and total area of the femur were determined by dual-energy X-ray absorptiometry (DXA). In the distal femur (cancellous bone-rich region), treatment with YM failed to restore BMD in OVX rats, while treatment with PTH alone (P<.01) or PTH + YM175 (P<.01) reversed BMD in OVX rats after 4 weeks of treatments. The restored distal BMD by PTH or PTH + YM175 treatments could be maintained thereafter until 12 weeks withdrawal. In midshaft of the femur (cortical bone-rich region), treatment with PTH (P<.05), YM175 (P<.05), and PTH + YM175 (P<.01) all could increase BMD after 4 weeks of treatments in the OVX rats, but only concurrent treatment with PTH + YM175 maintained the BMD of femoral midshaft for 12 weeks after withdrawal of the treatment. These results suggest that (1) concurrent treatment with PTH and YM175 could result in a bone gain not only in cancellous bone but also in cortical bone of the femur, and (2) the restored BMD could be maintained for 12 weeks after cessation of the treatment in cortical bone only by concurrent use of PTH + YM175 in immature ovariectomized rats     

A longitudinal HR‐pQCT study of alendronate treatment in postmenopausal women with low bone density: Relations among density,cortical and trabecular microarchitecture,biomechanics, and bone turnover

The goal of this study was to characterize longitudinal changes in bone microarchitecture and function in women treated with an established antifracture therapeutic. In this double‐blind, placebo‐controlled pilot study, 53 early postmenopausal women with low bone density (age = 56 ± 4 years; femoral neck T‐score = ?1.5 ± 0.6) were monitored by high‐resolution peripheral quantitative computed tomography (HR‐pQCT) for 24 months following randomization to alendronate (ALN) or placebo (PBO) treatment groups. Subjects underwent annual HR‐pQCT imaging of the distal radius and tibia, dual‐energy X‐ray absorptiometry (DXA), and determination of biochemical markers of bone turnover (BSAP and uNTx). In addition to bone density and microarchitecture assessment, regional analysis, cortical porosity quantification, and micro‐finite‐element analysis were performed. After 24 months of treatment, at the distal tibia but not the radius, HR‐pQCT measures showed significant improvements over baseline in the ALN group, particularly densitometric measures in the cortical and trabecular compartments and endocortical geometry (cortical thickness and area, medullary area) (p < .05). Cortical volumetric bone mineral density (vBMD) in the tibia alone showed a significant difference between treatment groups after 24 months (p < .05); however, regionally, significant differences in Tb.vBMD, Tb.N, and Ct.Th were found for the lateral quadrant of the radius (p < .05). Spearman correlation analysis revealed that the biomechanical response to ALN in the radius and tibia was specifically associated with changes in trabecular microarchitecture (|ρ| = 0.51 to 0.80, p < .05), whereas PBO progression of bone loss was associated with a broad range of changes in density, geometry, and microarchitecture (|ρ| = 0.56 to 0.89, p < .05). Baseline cortical geometry and porosity measures best predicted ALN‐induced change in biomechanics at both sites (ρ > 0.48, p < .05). These findings suggest a more pronounced response to ALN in the tibia than in the radius, driven by trabecular and endocortical changes. © 2010 American Society for Bone and Mineral Research.     

Effects of combined elcatonin and alendronate treatment on the architecture and strength of bone in ovariectomized rats

We examined the combined effects of elcatonin (ECT) and alendronate (ALN) on bone mass, architecture, and strength in ovariectomized (OVX) rats. Fifty female Sprague Dawley rats, aged 13 weeks, were divided into Sham, OVX, OVX+ECT, OVX+ALN, and OVX+ECT+ALN groups (n = 10). Immediately after ovariectomy, ECT was administered at a dose of 15 units (U)/kg three times a week, and ALN was administered daily at a dose of 2.0 µg/kg, subcutaneously for 12 weeks. The three-dimensional architecture of the bone in the distal femoral metaphysis was analyzed using a microfocus X-ray computed tomography system (µCT), and bone strength was measured using a material-testing machine. Trabe-cular bone volume (BV/TV) and number (Tb.N) were significantly greater in the OVX+ECT and OVX+ALN groups than in the OVX group. In the OVX+ECT+ALN group, BV/TV and Tb.N were significantly greater when compared with those in the OVX+ECT and OVX+ALN groups. Trabecular thickness (Tb.Th) was significantly greater in the OVX+ECT+ALN group than in the OVX+ALN group. With regard to bone strength, the compression strength in the femoral metaphysis was significantly lower in the OVX group than in the Sham group. The reduction of compression strength was slightly lower in the OVX+ECT and OVX+ALN groups. In the OVX+ECT+ALN group, the compression strength in the femoral metaphysis significantly increased when compared with the OVX and OVX+ECT groups. These results suggest that the combined treatment of ECT and ALN does not alter the individual effects of each drug and that it exerts an additive effect on trabecular architecture and bone strength in OVX rats.     

Three-dimensional Modeling of the Effects of Parathyroid Hormone on Bone Distribution in Lumbar Vertebrae of Ovariectomized Cynomolgus Macaques

Biomechanical and quantitative computed tomography (QCT) analyses showed beneficial effects of parathyroid hormone (PTH (1–34)) on lumbar vertebrae from ovariectomized monkeys, even after withdrawal of treatment for 6 months. Adult cynomolgus monkeys were randomized, ovariectomized (except for sham ovariectomy controls), and treated subcutaneously with vehicle (OVX) or 5 μg/kg per day PTH (1–34) (PTH5) for 18 months. An additional group was treated subcutaneously with 5 μg/kg per day PTH (1–34) (PTH5W) for 12 months and then switched to vehicle for the remaining 6 months. Lumbar vertebrae were excised at necropsy, and L5 were serially scanned by QCT, using 70 × 70 × 500 μm voxels. PTH increased volumetric bone mineral density (BMD, mg/cm³) and bone mineral content (BMC, mg) for both PTH5 and PTH5W compared with OVX and Sham without inducing hypermineralization, without stimulating periosteal expansion, and without significant constriction of the neural canal. BMD values for the voxels were then averaged to create nearly isotropic voxels of 490 × 490 × 500 μm. Serial scans were stacked and a triangular surface mesh generated for each bone, using a “marching cubes” algorithm. A smoothed version of each surface mesh was used to generate a tetrahedral element for three-dimensional finite element modeling. An isotropic Young”s modulus for each tetrahedral element was calculated as a function of the original voxel BMDs. Linear elastic stress analysis was then performed for each finite element model in which a distributed load of 100 newtons (N) was applied to the top surface of the centrum, perpendicular to the bottom surface with the bottom surface constrained in the direction of loading. Analysis of the effective strain showed considerable reduction in vertebral strain for both PTH5 and PTH5W, compared with OVX. Compression testing of the adjacent L3 and L4 confirmed that vertebral strength and stiffness for PTH5 and PTH5W were significantly greater than for OVX. Histogram and QCT analyses showed PTH conversion of low-density bone (trabecular bone) into medium-density bone (more and thicker trabeculae) by stimulating bone apposition. PTH withdrawal induced conversion of medium-density into low-density and high-density bone with the latter higher than in OVX. These data show that even transient PTH treatment improves vertebral architecture and bone quality to reduce the likelihood of fracture, and that transient treatment is better than no PTH treatment at all. Received: 11 January 2000 / Accepted: 17 April 2000     

Changes in intracortical microporosities induced by pharmaceutical treatment of osteoporosis as detected by high resolution micro-CT

Bone's microporosities play important biologic and mechanical roles. Here, we quantified 3D changes in cortical osteocyte-lacunae and other small porosities induced by estrogen withdrawal and two different osteoporosis treatments. Unlike 2D measurements, these data collected via synchrotron radiation-based μCT describe the size and 3D spatial distribution of a large number of porous structures. Six-month old female Sprague-Dawley rats were separated into four groups of age-matched controls, untreated OVX, OVX treated with PTH, and OVX treated with Alendronate (ALN). Intracortical microporosity of the medial quadrant of the femoral diaphysis was quantified at endosteal, intracortical, and periosteal regions of the samples, allowing the quantification of osteocyte lacunae that were formed primarily before versus after the start of treatment. Across the overall thickness of the medial cortex, lacunar volume fraction (Lc.V/TV) was significantly lower in ALN treated rats compared to PTH. In the endosteal region, average osteocyte lacunar volume () of untreated OVX rats was significantly lower than in age-matched controls, indicating a decrease in osteocyte lacunar size in bone formed on the endosteal surface after estrogen withdrawal. The effect of treatment (OVX, ALN, PTH) on the number of lacunae per tissue volume (Lc.N/TV) was dependent on the specific location within the cortex (endosteal, intracortical, periosteal). In both the endosteal and intracortical regions, Lc.N/TV was significantly lower in ALN than in untreated OVX, suggesting a site-specific effect in osteocyte lacuna density with ALN treatment. There also were a significantly greater number of small pores (5-100 μm(3) in volume) in the endosteal region for PTH compared to ALN. The mechanical impact of this altered microporosity structure is unknown, but might serve to enhance, rather than deteriorate bone strength with PTH treatment, as smaller osteocyte lacunae may be better able to absorb shear forces than larger lacunae. Together, these data demonstrate that current treatments of osteoporosis can alter the number, size, and distribution of microporosities in cortical rat lamellar bone.     

Effects of ovariectomy on bone turnover,porosity, and biomechanical properties in ovine compact bone 12 months postsurgery

Compact bone makes up approximately 80% of the human skeleton by mass; but there are little data available on the effects of increased bone turnover on compact bone mechanical and material properties. This study addresses this question by measuring intracortical remodeling, resorption cavity number, and porosity in an ovariectomized (OVX) sheep model, and measures changes in biomechanical properties. Thirty‐eight sheep were divided into two groups. Group 1 were controls (n = 19), and Group 2 were ovariectomized (OVX; n = 19). Fluorochrome dyes were administered intravenously to both groups at five time points over 12 months post‐OVX to label sites of bone turnover. At 12 months post‐OVX all animals were euthanized. Samples were harvested from the left metatarsal and were analyzed for intracortical bone turnover at five time points, the number of resorption cavities, and the level of intracortical porosity. The effects of these parameters on bone biomechanical properties were then measured. Bone turnover was increased in the OVX group at 6, 9, and 12 months (p < 0.05). Resorption was also higher in the OVX group at 12 months (p < 0.05). Furthermore, porosity was significantly increased in the OVX group at 12 months (p < 0.05). Stiffness and yield strength were reduced in the OVX group compared to controls (p = 0.05). Ultimate compressive strength and work to fracture did not differ between groups. These findings provide new insights into the mechanisms and effects of increased bone turnover on bone material and microstructural properties. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:303–309, 2009     

Effects of combination treatment with alendronate and vitamin K2 on bone mineral density and strength in ovariectomized mice

Bisphosphonates increase bone mineral density (BMD) by suppressing remodeling space and elongating the duration of mineralization. Menatetrenone (vitamin K₂) reduces the incidence of fractures by improving bone quality through enhanced γ-carboxylation of bone glutamic acid residues of osteocalcin in osteoporotic patients. This study investigated the effects of combination treatment with alendronate (ALN) and vitamin K₂ on BMD and bone strength in ovariectomized (OVX) mice. Thirty-three female mice, 16 weeks of age, were assigned to four groups: (1) OVX-control group; (2) oral vitamin K₂ group; (3) subcutaneous ALN group; and (4) ALN + vitamin K₂ group. The treatment was started 4 weeks after OVX and continued for 4 weeks. BMD, geometric parameters measured by peripheral quantitative computed tomography, and mechanical strength at the femoral metaphysis and mid-diaphysis were evaluated after an 8-week treatment period. ALN alone significantly increased total BMD (20%, P < 0.05) and trabecular BMD (25%, P < 0.05), but not the mechanical parameters of the femur, compared with the OVX-control group. Combination treatment with ALN and vitamin K₂ increased not only total BMD (15%, P < 0.05) and trabecular BMD (32%, P < 0.05) but also maximum load (33%, P < 0.05) and breaking energy (25%, P < 0.05) of compression test at the distal metaphysis, and maximum load (20%, P < 0.05) and breaking force (33%, P < 0.05) of three-point bending test at the mid-diaphysis compared with the OVX-control group. These results suggest that ALN, alone or in combination with vitamin K₂, showed significant improvement in BMD, but that the combination treatment was more effective than ALN alone for improving bone strength in OVX mice.     

Femoral Bone Strength and Its Relation to Cortical and Trabecular Changes After Treatment With PTH,Alendronate, and Their Combination as Assessed by Finite Element Analysis of Quantitative CT Scans

The “PTH and Alendronate” or “PaTH” study compared the effects of PTH(1‐84) and/or alendronate (ALN) in 238 postmenopausal, osteoporotic women. We performed finite element analysis on the QCT scans of 162 of these subjects to provide insight into femoral strength changes associated with these treatments and the relative roles of changes in the cortical and trabecular compartments on such strength changes. Patients were assigned to either PTH, ALN, or their combination (CMB) in year 1 and were switched to either ALN or placebo (PLB) treatment in year 2: PTH‐PLB, PTH‐ALN, CMB‐ALN, and ALN‐ALN (year 1‐year 2) treatments. Femoral strength was simulated for a sideways fall using nonlinear finite element analysis of the quantitative CT exams. At year 1, the strength change from baseline was statistically significant for PTH (mean, 2.08%) and ALN (3.60%), and at year 2, significant changes were seen for the PTH‐ALN (7.74%), CMB‐ALN (4.18%), and ALN‐ALN (4.83%) treatment groups but not for PTH‐PLB (1.17%). Strength increases were primarily caused by changes in the trabecular density regardless of treatment group, but changes in cortical density and mass also played a significant role, the degree of which depended on treatment. For PTH treatment at year 1 and for ALN‐ALN treatment at year 2, there were significant negative and positive strength effects, respectively, associated with a change in external bone geometry. Average changes in strength per treatment group were somewhat consistent with average changes in total hip areal BMD as measured by DXA, except for the PTH group at year 1. The relation between change in femoral strength and change in areal BMD was weak (r² = 0.14, pooled, year 2). We conclude that femoral strength changes with these various treatments were dominated by trabecular changes, and although changes in the cortical bone and overall bone geometry did contribute to femoral strength changes, the extent of these latter effects depended on the type of treatment.     

Low-magnitude high-frequency loading via whole body vibration enhances bone-implant osseointegration in ovariectomized rats

Osseointegration is vital to avoid long‐time implants loosening after implantation surgery. This study investigated the effect of low‐magnitude high‐frequency (LMHF) loading via whole body vibration on bone‐implant osseointegration in osteoporotic rats, and a comparison was made between LMHF vibration and alendronate on their effects. Thirty rats were ovariectomized to induce osteoporosis, and then treated with LMHF vibration (VIB) or alendronate (ALN) or a control treatment (OVX). Another 10 rats underwent sham operation to establish Sham control group. Prior to treatment, hydroxyapatite (HA)‐coated titanium implants were inserted into proximal tibiae bilaterally. Both LMHF vibration and alendronate treatment lasted for 8 weeks. Histomorphometrical assess showed that both group VIB, ALN and Sham significantly increased bone‐to‐implant contact and peri‐implant bone fraction (p < 0.05) when compared with group OVX. Nevertheless the bone‐to‐implant contact and peri‐implant bone fraction of group VIB were inferior to group ALN and Sham (p < 0.05). Biomechanical tests also revealed similar results in maximum push out force and interfacial shear strength. Accordingly, it is concluded that LMHF loading via whole body vibration enhances bone‐to‐implant osseointegration in ovariectomized rats, but its effectiveness is weaker than alendronate. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 30:733–739, 2012     

Effects of PTH and Alendronate on Type I Collagen Isomerization in Postmenopausal Women With Osteoporosis: The PaTH Study

Fracture efficacy of PTH and alendronate (ALN) is only partly explained by changes in BMD, and bone collagen properties have been suggested to play a role. We analyzed the effects of PTH(1–84) and ALN on urinary αα/ββ CTX ratio, a marker of type I collagen isomerization and maturation in postmenopausal women with osteoporosis. In the first year of the previously published PaTH study, postmenopausal women with osteoporosis were assigned to PTH(1–84) (100 μg/d; n = 119), ALN (10 mg/d; n = 60), or PTH and ALN together (n = 59). We analyzed patients on ALN alone (n = 60) and a similar number of patients assigned to PTH alone (n = 63). During the second year, women on PTH in the first year were reallocated to placebo (n = 31) or ALN (n = 32) and women with ALN continued on ALN. During the first year, there was no significant change in αα/ββ CTX ratio with PTH or ALN. At 24 mo, there was a marked increase of the αα/ββ CTX ratio in women who had received PTH during the first year, followed by a second year of placebo (median: +45.5, p < 0.001) or ALN (+55.2%, p < 0.001). Conversely, the αα/ββ CTX ratio only slightly increased (+16%, p < 0.05) after 2 yr of continued ALN. In conclusion, treatment with PTH(1–84) for 1 yr followed by 1 yr of placebo or ALN may be associated with decreased type I collagen isomerization. The influence of these biochemical changes of type I collagen on bone fracture resistance remains to be studied.     

Intermittent Parathyroid Hormone After Prolonged Alendronate Treatment Induces Substantial New Bone Formation and Increases Bone Tissue Heterogeneity in Ovariectomized Rats

Postmenopausal osteoporosis is often treated with bisphosphonates (eg, alendronate, [ALN]), but oversuppression of bone turnover by long‐term bisphosphonate treatment may decrease bone tissue heterogeneity. Thus, alternate treatment strategies after long‐term bisphosphonates are of great clinical interest. The objective of the current study was to determine the effect of intermittent parathyroid hormone (PTH) following 12 weeks of ALN (a bisphosphonate) treatment in 6‐month‐old, ovariectomized (OVX) rats on bone microarchitecture, bone remodeling dynamics, and bone mechanical properties at multiple length scales. By using in vivo μCT and 3D in vivo dynamic bone histomorphometry techniques, we demonstrated the efficacy of PTH following ALN therapy for stimulating new bone formation, and increasing trabecular thickness and bone volume fraction. In healthy bone, resorption and formation are coupled and balanced to sustain bone mass. OVX results in resorption outpacing formation, and subsequent bone loss and reduction in bone tissue modulus and tissue heterogeneity. We showed that ALN treatment effectively reduced bone resorption activity and regained the balance with bone formation, preventing additional bone loss. However, ALN treatment also resulted in significant reductions in the heterogeneity of bone tissue mineral density and tissue modulus. On the other hand, PTH treatment was able to shift the bone remodeling balance in favor of formation, with or without a prior treatment with ALN. Moreover, by altering the tissue mineralization, PTH alleviated the reduction in heterogeneity of tissue material properties induced by prolonged ALN treatment. Furthermore, switching to PTH treatment from ALN improved bone's postyield mechanical properties at both the whole bone and apparent level compared to ALN alone. The current findings suggest that intermittent PTH treatment should be considered as a viable treatment option for patients with prior treatment with bisphosphonates. © 2017 American Society for Bone and Mineral Research.     

Effects of Denosumab,Alendronate, or Denosumab Following Alendronate on Bone Turnover,Calcium Homeostasis,Bone Mass and Bone Strength in Ovariectomized Cynomolgus Monkeys

Postmenopausal osteoporosis is a chronic disease wherein increased bone remodeling reduces bone mass and bone strength. Antiresorptive agents including bisphosphonates are commonly used to mitigate bone loss and fracture risk. Osteoclast inhibition via denosumab (DMAb), a RANKL inhibitor, is a newer approach for reducing fracture risk in patients at increased risk for fracture. The safety of transitioning from bisphosphonate therapy (alendronate; ALN) to DMAb was examined in mature ovariectomized (OVX) cynomolgus monkeys (cynos). One day after OVX, cynos (7–10/group) were treated with vehicle (VEH, s.c.), ALN (50 μg/kg, i.v., twice monthly) or DMAb (25 mg/kg/month, s.c.) for 12 months. Other animals received VEH or ALN for 6 months and then transitioned to 6 months of DMAb. DMAb caused significantly greater reductions in serum CTx than ALN, and transition from ALN to DMAb caused further reductions relative to continued ALN. DMAb and ALN decreased serum calcium (Ca), and transition from ALN to DMAb resulted in a lesser decline in Ca relative to DMAb or to VEH‐DMAb transition. Bone histomorphometry indicated significantly reduced trabecular and cortical remodeling with DMAb or ALN. Compared with ALN, DMAb caused greater reductions in osteoclast surface, eroded surface, cortical porosity and fluorochrome labeling, and transition from ALN to DMAb reduced these parameters relative to continued ALN. Bone mineral density increased in all active treatment groups relative to VEH controls. Destructive biomechanical testing revealed significantly greater vertebral strength in all three groups receiving DMAb, including those receiving DMAb after ALN, relative to VEH controls. Bone mass and strength remained highly correlated in all groups at all tested skeletal sites, consistent with normal bone quality. These data indicate that cynos transitioned from ALN to DMAb exhibited reduced bone resorption and cortical porosity, and increased BMD and bone strength, without deleterious effects on Ca homeostasis or bone quality. © 2014 American Society for Bone and Mineral Research.     

Differing effects of PTH 1–34, PTH 1–84, and zoledronic acid on bone microarchitecture and estimated strength in postmenopausal women with osteoporosis: An 18‐month open‐labeled observational study using HR‐pQCT

Whereas the beneficial effects of intermittent treatment with parathyroid hormone (PTH) (intact PTH 1–84 or fragment PTH 1–34, teriparatide) on vertebral strength is well documented, treatment may not be equally effective in the peripheral skeleton. We used high‐resolution peripheral quantitative computed tomography (HR‐pQCT) to detail effects on compartmental geometry, density, and microarchitecture as well as finite element (FE) estimated integral strength at the distal radius and tibia in postmenopausal osteoporotic women treated with PTH 1–34 (20 µg sc daily, n = 18) or PTH 1–84 (100 µg sc daily, n = 20) for 18 months in an open‐label, nonrandomized study. A group of postmenopausal osteoporotic women receiving zoledronic acid (5 mg infusion once yearly, n = 33) was also included. Anabolic therapy increased cortical porosity in radius (PTH 1–34 32 ± 37%, PTH 1–84 39 ± 32%, both p < 0.001) and tibia (PTH 1–34 13 ± 27%, PTH 1–84 15 ± 22%, both p < 0.001) with corresponding declines in cortical density. With PTH 1–34, increases in cortical thickness in radius (2.0 ± 3.8%, p < 0.05) and tibia (3.8 ± 10.4%, p < 0.01) were found. Trabecular number increased in tibia with both PTH 1–34 (4.2 ± 7.1%, p < 0.05) and PTH 1–84 (5.3 ± 8.3%, p < 0.01). Zoledronic acid did not impact cortical porosity at either site but increased cortical thickness (3.0 ± 3.5%, p < 0.01), total (2.7 ± 2.5%, p < 0.001) and cortical density (1.5 ± 2.0%, p < 0.01) in tibia as well as trabecular volume fraction in radius (2.5 ± 5.1%, p < 0.05) and tibia (2.2 ± 2.2%, p < 0.01). FE estimated bone strength was preserved, but not increased, with PTH 1–34 and zoledronic acid at both sites, whereas it decreased with PTH 1–84 in radius (?2.8 ± 5.8%, p < 0.05) and tibia (–3.9 ± 4.8%, p < 0.001). Conclusively, divergent treatment‐specific effects in cortical and trabecular bone were observed with anabolic and zoledronic acid therapy. The finding of decreased estimated strength with PTH 1–84 treatment was surprising and warrants confirmation. © 2013 American Society for Bone and Mineral Research.