The Combination Therapy with Zoledronic Acid and Propranolol Improves the Trabecular Microarchitecture and Mechanical Property in an Rat Model of Postmenopausal Osteoporosis
We conducted the present study to investigate the therapeutic effects of propranolol (PRO), alone and in combination with the antiresorptive agent ZOL, in a rat model of postmenopausal osteoporosis. Female Wistar rats were OVX or sham-operated at 3 months of age. Twelve weeks after surgery, rats were randomized into six groups: (1) sham + vehicle, (2) OVX + vehicle, (3) OVX + ZOL (100？μg/kg, i.v. single dose), (4) OVX + ZOL (50？μg/kg, i.v. single dose), (5) OVX + PRO (0.1？mg/kg, s.c. 5 days per week), and (6) OVX + ZOL (50？μg/kg, i.v. single dose) + PRO (0.1？mg/kg, s.c. 5 days per week) for 12 weeks. At the end of treatment study, various bone parameters were evaluated. With respect to improvement in the mechanical strength of the lumbar spine and the femoral mid-shaft, the combination treatment of ZOL and PRO was more effective than each drug administered as a monotherapy. Moreover, combination therapy using ZOL and PRO preserved the trabecular microarchitecture better than single-drug therapy using ZOL or PRO in OVX rats. These data suggest that combination therapy with ZOL plus PRO represents a potentially useful therapeutic option for patients with osteoporosis. 1. Introduction Osteoporosis is a degenerative disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and increased fracture risk. Osteoporosis is considered an important public health issue increasing rapidly in the elderly population [1, 2]. The fractures caused by osteoporosis have clinical and public health impacts, as they are often associated with increased morbidity, mortality, and enormous healthcare expenditure [1]. For those already affected by osteoporosis, timely diagnosis of bone loss, assessment of fracture risk, and selection of optimal treatment at appropriate stages of the disease are very important for effective management of osteoporosis. Zoledronic acid (ZOL) is a third generation nitrogen-containing bisphosphonate that has been shown to significantly reduce the risk of fractures in patients who receive the once-yearly dosing regimen for the treatment of postmenopausal osteoporosis [3]. ZOL interferes with osteoclastic activity by inhibiting osteoclast formation and osteoclast bone resorptive activities and by inducing osteoclast apoptotic cell death. On osteoclast stimulation of bone resorption, the bisphosphonate is released and internalized by the osteoclasts, interfering with osteoclast formation, function, and survival [4–6]. Moreover, the results obtained from several histologic and
References
[1]
D. K. Khajuria, R. Razdan, and D. R. Mahapatra, “Drugs for the management of osteoporosis: a review,” Revista Brasileira de Reumatologia, vol. 51, no. 4, pp. 365–382, 2011.
[2]
M. H. Hohenhaus, K. A. McGarry, and N. F. Col, “Hormone therapy for the prevention of bone loss in menopausal women with osteopenia: is it a viable option?” Drugs, vol. 67, no. 16, pp. 2311–2321, 2007.
[3]
D. M. Black, P. D. Delmas, R. Eastell et al., “Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis,” New England Journal of Medicine, vol. 356, no. 18, pp. 1809–1822, 2007.
[4]
F. P. Coxon, M. H. Helfrich, R. Van't Hof et al., “Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298,” Journal of Bone and Mineral Research, vol. 15, no. 8, pp. 1467–1476, 2000.
[5]
O. S. Nielsen, A. J. Munro, and I. F. Tannock, “Bone metastases: pathophysiology and management policy,” Journal of Clinical Oncology, vol. 9, no. 3, pp. 509–524, 1991.
[6]
H. L. Benford, N. W. A. McGowan, M. H. Helfrich, M. E. Nuttall, and M. J. Rogers, “Visualization of bisphosphonate-induced caspase-3 activity in apoptotic osteoclasts in vitro,” Bone, vol. 28, no. 5, pp. 465–473, 2001.
[7]
J. A. Gasser, P. Ingold, A. Venturiere, V. Shen, and J. R. Green, “Long-term protective effects of zoledronic acid on cancellous and cortical bone in the ovariectomized rat,” Journal of Bone and Mineral Research, vol. 23, no. 4, pp. 544–551, 2008.
[8]
D. K. Khajuria, R. Razdan, D. R. Mahapatra, and M. R. Bhat, “Osteoprotective effect of propranolol in ovariectomized rats: a comparison with zoledronic acid and alfacalcidol,” Journal of Orthopaedic Science, vol. 18, no. 5, pp. 832–842, 2013.
[9]
D. K. Khajuria, C. Disha, R. Razdan, and D. R. Mahapatra, “Comparative evaluation of zoledronic acid, alfacalcidol, and propranolol in pharmacological correction of experimental osteoporosis,” Latin American Journal of Pharmacy, vol. 32, no. 7, pp. 968–976, 2013.
[10]
D. K. Khajuria, C. Disha, R. Razdan, D. R. Mahapatra, and R. Vasireddi, “Prophylactic effects of propranolol versus standard therapy on a new model of disuse osteoporosis in rats,” Scientia Pharmaceutica, 2013.
[11]
P. D. Papapetrou, “Bisphosphonate-associated adverse events,” Hormones, vol. 8, no. 2, pp. 96–110, 2009.
[12]
J. E. M. Brouwers, B. van Rietbergen, and M. L. Bouxsein, “Influence of early and late zoledronic acid administration on vertebral structure and strength in ovariectomized rats,” Calcified Tissue International, vol. 83, no. 3, pp. 186–191, 2008.
[13]
A. Togari and M. Arai, “Pharmacological topics of bone metabolism: the physiological function of the sympathetic nervous system in modulating bone resorption,” Journal of Pharmacological Sciences, vol. 106, no. 4, pp. 542–546, 2008.
[14]
S. Takeda and G. Karsenty, “Molecular bases of the sympathetic regulation of bone mass,” Bone, vol. 42, no. 5, pp. 837–840, 2008.
[15]
M. W. Hamrick and S. L. Ferrari, “Leptin and the sympathetic connection of fat to bone,” Osteoporosis International, vol. 19, no. 7, pp. 905–912, 2008.
[16]
N. Bonnet, C. L. Benhamou, L. Malaval et al., “Low dose beta-blocker prevents ovariectomy-induced bone loss in rats without affecting heart functions,” Journal of Cellular Physiology, vol. 217, no. 3, pp. 819–827, 2008.
[17]
T. Sato, M. Arai, S. Goto, and A. Togari, “Effects of propranolol on bone metabolism in spontaneously hypertensive rats,” Journal of Pharmacology and Experimental Therapeutics, vol. 334, no. 1, pp. 99–105, 2010.
[18]
C. E. Lezón, P. M. Pintos, M. I. Olivera, C. Bozzini, and P. M. Boyer, “Effect of different propranolol doses on skeletal structural and mechanic efficiency in an animal model of growth retardation,” Endocrinologia y Nutricion, vol. 59, no. 1, pp. 9–20, 2012.
[19]
N. Bonnet, C. Gadois, E. McCloskey et al., “Protective effect of β blockers in postmenopausal women: influence on fractures, bone density, micro and macroarchitecture,” Bone, vol. 40, no. 5, pp. 1209–1216, 2007.
[20]
F. de Vries, P. C. Souverein, C. Cooper, H. G. M. Leufkens, and T. P. van Staa, “Use of β-blockers and the risk of hip/femur fracture in the United Kingdom and The Netherlands,” Calcified Tissue International, vol. 80, no. 2, pp. 69–75, 2007.
[21]
C. Meisinger, M. Heier, O. Lang, and A. D？ring, “β-blocker use and risk of fractures in men and women from the general population: the MONICA/KORA Augsburg cohort study,” Osteoporosis International, vol. 18, no. 9, pp. 1189–1195, 2007.
[22]
J. D. Ringe, “Combination therapy in osteoporosis: basic therapy plus specific osteoporosis drug,” Medizinische Monatsschrift fur Pharmazeuten, vol. 32, no. 4, pp. 137–140, 2009.
[23]
H. Sasaki, N. Miyakoshi, Y. Kasukawa et al., “Effects of combination treatment with alendronate and vitamin K2 on bone mineral density and strength in ovariectomized mice,” Journal of Bone and Mineral Metabolism, vol. 28, no. 4, pp. 403–409, 2010.
[24]
W. F. Rodrigues, M. F. M. Madeira, T. A. da Silva et al., “Low dose of propranolol down-modulates bone resorption by inhibiting inflammation and osteoclast differentiation,” British Journal of Pharmacology, vol. 165, no. 7, pp. 2140–2151, 2012.
[25]
H. H. Huang, T. C. Brennan, M. M. Muir, and R. S. Mason, “Functional α1- and β2-adrenergic receptors in human osteoblasts,” Journal of Cellular Physiology, vol. 220, no. 1, pp. 267–275, 2009.
[26]
D. K. Khajuria, R. Razdan, and D. R. Mahapatra, “Description of a new method of ovariectomy in female rats,” Revista Brasileira de Reumatologia, vol. 52, no. 3, pp. 466–470, 2012.
[27]
Z. Cheng, W. Yao, E. A. Zimmermann, C. Busse, R. O. Ritchie, and N. E. Lane, “Prolonged treatments with antiresorptive agents and PTH have different effects on bone strength and the degree of mineralization in old estrogen-deficient osteoporotic rats,” Journal of Bone and Mineral Research, vol. 24, no. 2, pp. 209–220, 2009.
[28]
O. V. Lepp？nen, H. Siev？nen, and T. L. J？rvinen, “Biomechanical testing in experimental bone interventions—may the power be with you,” Journal of Biomechanics, vol. 4, no. 8, pp. 1623–1631, 2008.
[29]
R. Bergner, I. J. Diel, D. Henrich, M. Hoffmann, and M. Uppenkamp, “Differences in nephrotoxicity of intravenous bisphosphonates for the treatment of malignancy-related bone disease,” Onkologie, vol. 29, no. 11, pp. 534–540, 2006.
[30]
D. M. Black, P. D. Delmas, R. Eastell et al., “Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis,” New England Journal of Medicine, vol. 356, no. 18, pp. 1809–1822, 2007.
[31]
S. Lévy, “Pharmacologic management of atrial fibrillation: current therapeutic strategies,” American Heart Journal, vol. 141, no. 2, pp. S15–S21, 2001.
[32]
B. I. Ray, “Atrial fibrillation: present treatment protocols by drugs and interventions,” Journal of the Indian Academy of Clinical Medicine, vol. 4, no. 3, pp. 213–227, 2003.
