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Published in: Journal of Orthopaedic Science 4/2014

01-07-2014 | Original Article

Zoledronic acid in combination with alfacalcidol has additive effects on trabecular microarchitecture and mechanical properties in osteopenic ovariectomized rats

Authors: Deepak Kumar Khajuria, Rema Razdan, Debiprosad Roy Mahapatra

Published in: Journal of Orthopaedic Science | Issue 4/2014

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Abstract

Background

We conducted the present study to investigate the therapeutic effects of the antiresorptive agent zoledronic acid (ZOL), alone and in combination with alfacalcidol (ALF), in a rat model of postmenopausal osteoporosis.

Methods

Female Wistar rats were ovariectomized (OVX) or sham-operated at 3 months of age. Twelve weeks post 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 + ALF (0.5 μg/kg, oral gauge daily) and (6) OVX + ZOL (50 μg/kg, i.v. single dose) + ALF (0.5 μg/kg, oral gauge daily) for 12 weeks. After treatment, we evaluated the mechanical properties of the lumbar vertebra and femoral mid-shaft. Femurs were also tested for bone density, porosity and trabecular micro-architecture. Biochemical markers in serum and urine were also determined.

Results

With respect to improvement in the mechanical strength of the lumbar spine and the femoral mid-shaft, the combination treatment of ZOL and ALF was more effective than each administered as a monotherapy. Moreover, combination therapy using ZOL and ALF preserved the trabecular micro-architecture and cortical bone porosity. Furthermore, the combination treatment of ZOL and ALF corrected the decrease in serum calcium and increase in serum alkaline phosphatase and the tartarate-resistant acid phosphatase level better than single-drug therapy using ZOL or ALF in OVX rats. In addition, the combination treatment of ZOL and ALF corrected the increase in urine calcium, phosphorous and creatinine levels better than single-drug therapy using ZOL or ALF in OVX rats.

Conclusions

These data suggest that the combination treatment of ZOL and ALF has a therapeutic advantage over each monotherapy for the treatment of osteoporosis.
Literature
1.
go back to reference Khajuria DK, Razdan R, Mahapatra DR. Drugs for the management of osteoporosis: a review. Rev Bras Reumatol. 2011;51:365–82.PubMedCrossRef Khajuria DK, Razdan R, Mahapatra DR. Drugs for the management of osteoporosis: a review. Rev Bras Reumatol. 2011;51:365–82.PubMedCrossRef
2.
go back to reference Hohenhaus MH, McGarry KA, Col NF. Hormone therapy for the prevention of bone loss in menopausal women with osteopenia: is it a viable option? Drugs. 2007;67:2311–21.PubMedCrossRef Hohenhaus MH, McGarry KA, Col NF. Hormone therapy for the prevention of bone loss in menopausal women with osteopenia: is it a viable option? Drugs. 2007;67:2311–21.PubMedCrossRef
3.
go back to reference Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809–22.PubMedCrossRef Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809–22.PubMedCrossRef
4.
go back to reference Coxon FP, Helfrich MH, Van’t Hof R, Sebti S, Ralston SH, Hamilton A, Rogers MJ. Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J Bone Miner Res. 2000;15:1467–76.PubMedCrossRef Coxon FP, Helfrich MH, Van’t Hof R, Sebti S, Ralston SH, Hamilton A, Rogers MJ. Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J Bone Miner Res. 2000;15:1467–76.PubMedCrossRef
5.
go back to reference Nielson OS, Munro AJ, Tannock IF. Bone metastasis: pathophysiology and management policy. J Clin Oncol. 1991;9:509–24. Nielson OS, Munro AJ, Tannock IF. Bone metastasis: pathophysiology and management policy. J Clin Oncol. 1991;9:509–24.
6.
go back to reference Benford HL, McGowan NW, Helfrich MH, Nuttall ME, Rogers MJ. Visualization of bisphosphonate induced caspase-3 activity in apoptotic osteoclasts in vitro. Bone. 2001;28:465–73.PubMedCrossRef Benford HL, McGowan NW, Helfrich MH, Nuttall ME, Rogers MJ. Visualization of bisphosphonate induced caspase-3 activity in apoptotic osteoclasts in vitro. Bone. 2001;28:465–73.PubMedCrossRef
7.
go back to reference Khajuria DK, Razdan R, Mahapatra DR, Bhat MR. Osteoprotective effect of propranolol in ovariectomized rats: a comparison with zoledronic acid and alfacalcidol. J Orthop Sci. 2013;18:832–42.PubMedCrossRef Khajuria DK, Razdan R, Mahapatra DR, Bhat MR. Osteoprotective effect of propranolol in ovariectomized rats: a comparison with zoledronic acid and alfacalcidol. J Orthop Sci. 2013;18:832–42.PubMedCrossRef
8.
go back to reference Khajuria DK, Disha C, Razdan R, Mahapatra DR. Comparative evaluation of zoledronic acid, alfacalcidol, and propranolol in pharmacological correction of experimental osteoporosis. Lat Am J Pharm. 2013;32:968–76. Khajuria DK, Disha C, Razdan R, Mahapatra DR. Comparative evaluation of zoledronic acid, alfacalcidol, and propranolol in pharmacological correction of experimental osteoporosis. Lat Am J Pharm. 2013;32:968–76.
9.
go back to reference Khajuria DK, Disha C, Razdan R, Mahapatra DR, Vasireddi R. Prophylactic effects of propranolol versus standard therapy on a new model of disuse osteoporosis in rats. Sci Pharm. 2014. doi:10.3797/scipharm.1310-06. Khajuria DK, Disha C, Razdan R, Mahapatra DR, Vasireddi R. Prophylactic effects of propranolol versus standard therapy on a new model of disuse osteoporosis in rats. Sci Pharm. 2014. doi:10.​3797/​scipharm.​1310-06.
10.
go back to reference Izawa Y, Makita T, Hino S, Hashimoto Y, Kushida K, Inoue T, Orimo H. Immobilization osteoporosis and active vitamin D: effect of active vitamin D analogs on the development of immobilization osteoporosis in rats. Calcif Tissue Int. 1981;33:623–30.PubMedCrossRef Izawa Y, Makita T, Hino S, Hashimoto Y, Kushida K, Inoue T, Orimo H. Immobilization osteoporosis and active vitamin D: effect of active vitamin D analogs on the development of immobilization osteoporosis in rats. Calcif Tissue Int. 1981;33:623–30.PubMedCrossRef
11.
go back to reference Ringe JD. Combination treatment in osteoporosis. Basic treatment plus specific osteoporosis medication. Med Monatsschr Pharm. 2009;32:137–40.PubMed Ringe JD. Combination treatment in osteoporosis. Basic treatment plus specific osteoporosis medication. Med Monatsschr Pharm. 2009;32:137–40.PubMed
12.
go back to reference Sasaki H, Miyakoshi N, Kasukawa Y, Maekawa S, Noguchi H, Kamo K, Shimada Y. Effects of combination treatment with alendronate and vitamin K (2) on bone mineral density and strength in ovariectomized mice. J Bone Miner Metab. 2010;28:403–9.PubMedCrossRef Sasaki H, Miyakoshi N, Kasukawa Y, Maekawa S, Noguchi H, Kamo K, Shimada Y. Effects of combination treatment with alendronate and vitamin K (2) on bone mineral density and strength in ovariectomized mice. J Bone Miner Metab. 2010;28:403–9.PubMedCrossRef
13.
go back to reference Sakai S, Endo K, Takeda S, Mihara M, Shiraishi A. Combination therapy with alendronate and eldecalcitol has therapeutic advantages over monotherapy by improving bone strength. Bone. 2012;50:1054–63.PubMedCrossRef Sakai S, Endo K, Takeda S, Mihara M, Shiraishi A. Combination therapy with alendronate and eldecalcitol has therapeutic advantages over monotherapy by improving bone strength. Bone. 2012;50:1054–63.PubMedCrossRef
14.
go back to reference Schacht E, Dukas L, Richy F. Combined therapies in osteoporosis: bisphosphonates and vitamin D-hormone analogs. J Musculoskelet Neuronal Interact. 2007;7:174–84.PubMed Schacht E, Dukas L, Richy F. Combined therapies in osteoporosis: bisphosphonates and vitamin D-hormone analogs. J Musculoskelet Neuronal Interact. 2007;7:174–84.PubMed
15.
go back to reference Ringe JD, Farahmand P, Schacht E, Rozehnal A. Superiority of a combined treatment of alendronate and alfacalcidol compared to the combination of alendronate and plain vitamin D or alfacalcidol alone in established postmenopausal or male osteoporosis (AAC-Trial). Rheumatol Int. 2007;27:425–34.PubMedCrossRef Ringe JD, Farahmand P, Schacht E, Rozehnal A. Superiority of a combined treatment of alendronate and alfacalcidol compared to the combination of alendronate and plain vitamin D or alfacalcidol alone in established postmenopausal or male osteoporosis (AAC-Trial). Rheumatol Int. 2007;27:425–34.PubMedCrossRef
16.
go back to reference Erben RG, Mosekilde L, Thomsen JS, Weber K, Stahr K, Leyshon A, Smith SY, Phipps R. Prevention of bone loss in ovariectomized rats by combined treatment with risedronate and 1α,25-dihydroxyvitamin D3. J Bone Miner Res. 2002;17:1498–511.PubMedCrossRef Erben RG, Mosekilde L, Thomsen JS, Weber K, Stahr K, Leyshon A, Smith SY, Phipps R. Prevention of bone loss in ovariectomized rats by combined treatment with risedronate and 1α,25-dihydroxyvitamin D3. J Bone Miner Res. 2002;17:1498–511.PubMedCrossRef
17.
go back to reference Khajuria DK, Razdan R, Mahapatra DR. Description of a new method of ovariectomy in female rats. Rev Bras Reumatol. 2012;52:466–70.CrossRef Khajuria DK, Razdan R, Mahapatra DR. Description of a new method of ovariectomy in female rats. Rev Bras Reumatol. 2012;52:466–70.CrossRef
18.
go back to reference Janckila AJ, Takahashi K, Sun SZ, Yam LT. Tartrate-resistant acid phosphatase isoform 5b as serum marker for osteoclastic activity. Clin Chem. 2001;47:74–80.PubMed Janckila AJ, Takahashi K, Sun SZ, Yam LT. Tartrate-resistant acid phosphatase isoform 5b as serum marker for osteoclastic activity. Clin Chem. 2001;47:74–80.PubMed
19.
go back to reference Riis BJ. The role of bone turnover in the pathophysiology of osteoporosis. Br J Obstet Gynaecol. 1996;103(Suppl. 13):9–15.PubMed Riis BJ. The role of bone turnover in the pathophysiology of osteoporosis. Br J Obstet Gynaecol. 1996;103(Suppl. 13):9–15.PubMed
20.
go back to reference Christiansen C, Riss BJ, Rodbro P. Screening procedure for women at risk of developing post menopausal osteoporosis. Osteoporos Int. 1990;1:35–40.PubMedCrossRef Christiansen C, Riss BJ, Rodbro P. Screening procedure for women at risk of developing post menopausal osteoporosis. Osteoporos Int. 1990;1:35–40.PubMedCrossRef
21.
go back to reference Hansen MA, Overgaard K, Riis BJ, Christiansen C. Role of peak bone mass and bone loss in postmenopausal osteoporosis. Br Med J. 1991;303:961–4.CrossRef Hansen MA, Overgaard K, Riis BJ, Christiansen C. Role of peak bone mass and bone loss in postmenopausal osteoporosis. Br Med J. 1991;303:961–4.CrossRef
22.
go back to reference Qureshi HJ, Hussain G, Jafary ZA, Bashir MU, Latif N, Riaz Z. Calcium status in premenopausal and postmenopausal women. J Ayub Med Coll Abbottabad. 2010;22:143–5.PubMed Qureshi HJ, Hussain G, Jafary ZA, Bashir MU, Latif N, Riaz Z. Calcium status in premenopausal and postmenopausal women. J Ayub Med Coll Abbottabad. 2010;22:143–5.PubMed
23.
go back to reference Yogesh HS, Chandrashekhar VM, Katti HR, Ganapaty S, Raghavendra HL, Gowda GK, Goplakhrishna B. Anti-osteoporotic activity of aqueous-methanol extract of Berberis aristata in ovariectomized rats. J Ethnopharmacol. 2011;134:334–8.PubMedCrossRef Yogesh HS, Chandrashekhar VM, Katti HR, Ganapaty S, Raghavendra HL, Gowda GK, Goplakhrishna B. Anti-osteoporotic activity of aqueous-methanol extract of Berberis aristata in ovariectomized rats. J Ethnopharmacol. 2011;134:334–8.PubMedCrossRef
24.
go back to reference Kalu DK, Liu CC, Salerno E. Skeletal response of ovariectomized rats to low and high doses of 17β-estradiol. Bone Miner. 1991;1991(14):175–87. Kalu DK, Liu CC, Salerno E. Skeletal response of ovariectomized rats to low and high doses of 17β-estradiol. Bone Miner. 1991;1991(14):175–87.
25.
go back to reference Das AS, Mukherjee M, Mitra C. Evidence for a prospective anti-osteoporosis effect of black tea (Camellia sinensis) extract in a bilaterally ovariectomized rat model. Asia Pac J Clin Nutr. 2004;13(2):210–6.PubMed Das AS, Mukherjee M, Mitra C. Evidence for a prospective anti-osteoporosis effect of black tea (Camellia sinensis) extract in a bilaterally ovariectomized rat model. Asia Pac J Clin Nutr. 2004;13(2):210–6.PubMed
26.
go back to reference Cheng Z, Yao W, Zimmermann EA, Busse C, Ritchie RO, Lane NE. Prolonged treatments with antiresorptive agents and PTH have different effects on bone strength and the degree of mineralization in old estrogen-deficient osteoporotic rats. J Bone Miner Res. 2009;24:209–20.PubMedCentralPubMed Cheng Z, Yao W, Zimmermann EA, Busse C, Ritchie RO, Lane NE. Prolonged treatments with antiresorptive agents and PTH have different effects on bone strength and the degree of mineralization in old estrogen-deficient osteoporotic rats. J Bone Miner Res. 2009;24:209–20.PubMedCentralPubMed
Metadata
Title
Zoledronic acid in combination with alfacalcidol has additive effects on trabecular microarchitecture and mechanical properties in osteopenic ovariectomized rats
Authors
Deepak Kumar Khajuria
Rema Razdan
Debiprosad Roy Mahapatra
Publication date
01-07-2014
Publisher
Springer Japan
Published in
Journal of Orthopaedic Science / Issue 4/2014
Print ISSN: 0949-2658
Electronic ISSN: 1436-2023
DOI
https://doi.org/10.1007/s00776-014-0557-8

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