Peri-Implant Bone Turnover in a Rat Model

Improving implant fixation is of growing interest due to the increased prevalence of joint replacement and the problem of implant loosening. Sclerostin antibody (scl-ab) has previously been shown to enhance implant fixation in rat models. Here, we test the hypothesis that scl-ab treatment increases bone formation and decreases resorption at the peri-implant periosteal, endocortical and trabecular surfaces and at the marrow-facing and implant-facing surfaces of the collar of bone typically found immediately adjacent to the implant. 4.5-month old Sprague-Dawley rats received sham-ovx or ovx followed by bilateral femoral intramedullary titanium rod insertion in the distal femur 6.5 months later. The rats were randomized to twice-weekly saline or scl-ab injection (25mg/kg) groups that were terminated at 4, 8 or 12 weeks or to a discontinued scl-ab dosing group (2 wks on/2 wks off, 4/4, and 8/4) (18 groups total with n = 7-9/group). The effect of ovariectomy (ovx) was assessed on baseline-control rats that did not receive an implant. Ovx resulted in decreased Tb.BV/TV and increased turnover. The effect of the implant was evaluated by comparing 4-week saline rats to baseline controls. The implant did not affect Tb.BV/TV and increased bone turnover in sham-ovx and ovx, demonstrating the regional acceleratory phenomenon. Scl-ab increased rates of bone formation and decreased resorption at all surfaces compared to saline controls. The bone formation rate was stable over time in saline controls but decreased in scl-ab throughout rats. Additionally, after 4 weeks of scl-ab withdrawal, the rates of bone formation tended to return to saline control levels. Despite this, ES/BS was rarely increased and Tb.BV/TV rarely decreased compared to scl-ab throughout. Additionally, scl-ab treatment generally increased BIC compared to saline. The results of this study indicate that scl-ab increases bone volume, bone formation rate and BIC while decreasing ES/BS.

Year	Entry
2009	Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, Gao Y, Shalhoub V, Tipton B, Haldankar R, Chen Q, Winters A, Boone T, Geng Z, Niu Q-T, Ke HZ, Kostenuik PJ, Simonet WS, Lacey DL, Paszty C. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res. April 2009;24(4):578-588.
1978	Uhthoff HK, Jaworski ZF. Bone loss in response to long-term immobilisation. J Bone Joint Surg. August 1978;60B(3):420-429.
1969	Frost HM. Tetracycline-based histological analysis of bone remodeling. Calcif Tiss Res. 1969;3(1):211-237.
1983	Frost HM. The regional acceleratory phenomenon: a review. Henry Ford Hosp Med J. 1983;31(1):3-9.
1989	Wronski TJ, Dann LM, Scott KS, Cintrón M. Long-term effects of ovariectomy and aging on the rat skeleton. Calcif Tiss Int. December 1989;45(6):360-366.
2010	Ominsky MS, Vlasseros F, Jolette J, Smith SY, Stouch B, Doellgast G, Gong J, Gao Y, Cao J, Graham K, Tipton B, Cai J, Deshpande R, Zhou L, Hale MD, Lightwood DJ, Henry AJ, Popplewell AG, Moore AR, Robinson MK, Lacey DL, Simonet WS, Paszty C. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J Bone Miner Res. May 2010;25(5):948-959.
1995	Manolagas SC, Jilka RL. Bone marrow, cytokines, and bone remodeling: emerging insights into the pathophysiology of osteoporosis. NEJM. February 2, 1995;332(5):305-311.
2001	Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den J Ende, Willems P, Paes-Alves AF, Hill S, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, Stratakis C, Lindpaintner K, Vickery B, Foernzler D, Van Hul W. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet. March 1, 2001;10(5):537-543.
2000	Teitelbaum SL. Bone resorption by osteoclasts. Science. September 1, 2000;289(5484):1504-1508.
2009	Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. NEJM. August 20, 2009;361(8):756-765.
1991	Kalu DN. The ovariectomized rat model of postmenopausal bone loss. Bone Miner. December 1991;15(3):175-191.
2008	Bonewald LF, Johnson ML. Osteocytes, mechanosensing and Wnt signaling. Bone. April 2008;42(4):606-615.
2001	van Staa TP, Dennison EM, Leufkens HGM, Cooper C. Epidemiology of fractures in England and Wales. Bone. January 2001;29(6):517-522.
1988	Parfitt AM. Bone histomorphometry: proposed system for standardization of nomenclature, symbols, and units. Calcif Tiss Int. May 1988;42(5):284-286.
1988	Recker RR, Kimmel DB, Parfitt MA, Davies MK, Keshawarz N, Hinders S. Static and tetracycline‐based bone histomorphometric data from 34 normal postmenopausal females. J Bone Miner Res. April 1988;3(2):133-344.
1988	Wronski TJ, Cintrón M, Dann LM. Temporal relationship between bone loss and increased bone turnover in ovariectomized rats. Calcif Tiss Int. September 1988;43(3):179-183.
1996	Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. December 7, 1996;348(9041):1535-1541.
2002	Ehrlich PJ, Lanyon LE. Mechanical strain and bone cell function: a review. Osteoporos Int. September 2002;13(9):688-700.
2006	Rodda SJ, McMahon AP. Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development. August 15, 2006;133(16):3231-3244.
2009	Lin C, Jiang X, Dai Z, Guo X, Weng T, Wang J, Li Y, Feng G, Gao X, He L. Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/β‐catenin signaling. J Bone Miner Res. October 2009;24(10):1651-1661.
2003	Frost HM. Bone's mechanostat: a 2003 update. Anat Rec. 2003;275A(2):1081-1101.
2003	Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, Shpektor D, Jonas M, Kovacevich BR, Staehling-Hampton K, Appleby M, Brunkow ME, Latham JA. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. January 2003;22(23):6267-6276.
2010	Papaioannou A, Morin S, Cheung AM, Atkinson S, Brown JP, Feldman S, Hanley DA, Hodsman A, Jamal SA, Kaiser SM, Kvern B, Siminoski K, Leslie WD; Scientific Advisory Council of Osteoporosis Canada. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. Can Med Assoc J. November 23, 2010;182(17):1864-1873.

Year

Entry

2009

Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, Gao Y, Shalhoub V, Tipton B, Haldankar R, Chen Q, Winters A, Boone T, Geng Z, Niu Q-T, Ke HZ, Kostenuik PJ, Simonet WS, Lacey DL, Paszty C. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res. April 2009;24(4):578-588.

1978

Uhthoff HK, Jaworski ZF. Bone loss in response to long-term immobilisation. J Bone Joint Surg. August 1978;60B(3):420-429.

1969

Frost HM. Tetracycline-based histological analysis of bone remodeling. Calcif Tiss Res. 1969;3(1):211-237.

1983

Frost HM. The regional acceleratory phenomenon: a review. Henry Ford Hosp Med J. 1983;31(1):3-9.

1989

Wronski TJ, Dann LM, Scott KS, Cintrón M. Long-term effects of ovariectomy and aging on the rat skeleton. Calcif Tiss Int. December 1989;45(6):360-366.