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Zoledronate and Raloxifene combination therapy enhances material and mechanical properties of diseased mouse bone.

ABSTRACT: Current interventions to reduce skeletal fragility are insufficient at enhancing both the quantity and quality of bone when attempting to improve overall mechanical integrity. Bisphosphonates, such as Zoledronate (ZOL), are used to treat a variety of bone disorders by increasing bone mass to decrease fracture risk, but long-term use has been shown in some settings to compromise bone quality. Alternatively, Raloxifene (RAL) has recently been demonstrated to improve tissue quality and overall mechanical properties in a cell-independent manner by binding to collagen and increasing tissue hydration. We hypothesized that a combination of RAL and ZOL would improve mechanical and material properties of bone more than either monotherapy alone by enhancing both quantity and quality. In this study, wildtype (WT) and heterozygous (OIM+/-) male mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL, ZOL, or both from 8?weeks to 16?weeks of age. Using the OIM model allows for investigation of therapeutic effects on a quality-based bone disease. Combination treatment resulted in higher trabecular architecture, cortical mechanical properties, and cortical fracture toughness in diseased mouse bone. Two fracture toughness properties, which are direct measures of the tissue's ability to resist the initiation and propagation of a crack, were significantly improved with combination treatment in OIM+/- compared to control. There was no significant effect on fracture toughness with either monotherapy alone in either genotype. Following the mass-based effects of ZOL, trabecular bone volume fraction was significantly higher with combination treatment in both genotypes. Combination treatment resulted in higher ultimate stress in both genotypes. RAL and combination treatment in OIM+/- also increased resilience compared to the control. In conclusion, this study demonstrates the beneficial effects of using combination drug treatments to increase bone mass while simultaneously improving tissue quality, especially to enhance the mechanical integrity of diseased bone. Combination therapies could be a potential method to improve bone health and combat skeletal fragility on both the microscopic and macroscopic levels.

SUBMITTER: Powell KM

PROVIDER: S-EPMC7036744 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Zoledronate and Raloxifene combination therapy enhances material and mechanical properties of diseased mouse bone.

Powell Katherine M KM Skaggs Cayla C Pulliam Alexis A Berman Alycia A Allen Matthew R MR Wallace Joseph M JM

Bone 20190621

Current interventions to reduce skeletal fragility are insufficient at enhancing both the quantity and quality of bone when attempting to improve overall mechanical integrity. Bisphosphonates, such as Zoledronate (ZOL), are used to treat a variety of bone disorders by increasing bone mass to decrease fracture risk, but long-term use has been shown in some settings to compromise bone quality. Alternatively, Raloxifene (RAL) has recently been demonstrated to improve tissue quality and overall mech ...[more]

PMID: 31233931

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Project description:Raloxifene (RAL) is an FDA-approved drug used to treat osteoporosis in postmenopausal women. RAL suppresses bone loss primarily through its role as a selective estrogen receptor modulator (SERM). This hormonal estrogen therapy promotes unintended side effects, such as hot flashes and increased thrombosis risk, and prevents the drug from being used in some patient populations at-risk for fracture, including children with bone disorders. It has recently been demonstrated that RAL can have significant positive effects on overall bone mechanical properties by binding to collagen and increasing bone tissue hydration in a cell-independent manner. A Raloxifene-Analog (RAL-A) was synthesized by replacing the 6-hydroxyl substituent with 6-methoxy in effort to reduce the compound's binding affinity for estrogen receptors (ER) while maintaining its collagen-binding ability. It was hypothesized that RAL-A would improve the mechanical integrity of bone in a manner similar to RAL, but with reduced estrogen receptor binding. Molecular assessment showed that while RAL-A did reduce ER binding, downstream ER signaling was not completely abolished. In-vitro, RAL-A performed similarly to RAL and had an identical concentration threshold on osteocyte cell proliferation, differentiation, and function. To assess treatment effect in-vivo, wildtype (WT) and heterozygous (OIM+/-) female mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL or RAL-A from 8 weeks to 16 weeks of age. There was an untreated control group for each genotype as well. Bone microarchitecture was assessed using microCT, and mechanical behavior was assessed using 3-point bending. Results indicate that both compounds produced analogous gains in tibial trabecular and cortical microarchitecture. While WT mechanical properties were not drastically altered with either treatment, OIM+/- mechanical properties were significantly enhanced, most notably, in post-yield properties including bone toughness. This proof-of-concept study shows promising results and warrants the exploration of additional analog iterations to further reduce ER binding and improve fracture resistance.

Project description:IntroductionThe effect of chronic patellar tendinopathy on tissue function and integrity is currently unclear and underinvestigated. The aim of this cohort comparison was to examine morphological, material, and mechanical properties of the patellar tendon and to extend earlier findings by measuring the ability to store and return elastic energy in symptomatic tendons.MethodsSeventeen patients with chronic (>3 months, VISA-P < 80), inferior pole patellar tendinopathy (24 ± 4 years; male = 12, female = 5) were carefully matched to controls (25 ± 3 years) for training status, pattern, and history of loading of the patellar tendon. Individual knee extension force, patellar tendon stiffness, stress, strain, Young's modulus, hysteresis, and energy storage capacity, were obtained with combined dynamometry, ultrasonography, magnetic resonance imaging, and electromyography.ResultsAnthropometric parameters did not differ between groups. VISA-P scores ranged from 28 to 78 points, and symptoms had lasted from 10 to 120 months before testing. Tendon proximal cross-sectional area was 61% larger in the patellar tendinopathy group than in the control group. There were no differences between groups in maximal voluntary isometric knee extension torque (p = 0.216; d < -0.31) nor in tensile tendon force produced during isometric ramp contractions (p = 0.185; d < -0.34). Similarly, tendon strain (p = 0.634; d < 0.12), hysteresis (p = 0.461; d < 0.18), and strain energy storage (p = 0.656; d < 0.36) did not differ between groups. However, patellar tendon stiffness (-19%; p = 0.007; d < -0.74), stress (-27%; p< 0.002; d < -0.90) and Young's modulus (-32%; p = 0.001; d < -0.94) were significantly lower in tendinopathic patients compared to healthy controls.DiscussionIn this study, we observed lower stiffness in affected tendons. However, despite the substantial structural and histological changes occurring with tendinopathy, the tendon capacity to store and dissipate energy did not differ significantly.

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Zoledronate and Raloxifene combination therapy enhances material and mechanical properties of diseased mouse bone.

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Zoledronate and Raloxifene combination therapy enhances material and mechanical properties of diseased mouse bone.

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