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. Author manuscript; available in PMC: 2019 May 1.
Published in final edited form as: Osteoporos Int. 2018 Apr 7;29(5):1009–1022. doi: 10.1007/s00198-018-4507-8

Table 1.

Pre-clinical studies of Anabolic agent effects

Clinical
Conditions		 Animal
Model		 Groups Results Reference
Spine Fusion Rat

  • Control;

  • ZA; TPTD 60 µg/kg/2d;

  • ZA + TPTD 60 µg/kg/2d

  • ZA and TPTD monotherapy increased bone volume at fusion site, and ZA+TPTD combined therapy had an additive effect vs control

  • TPTD and ZA+TPTD increased bone fusion rate vs control group

 Yishake 2017 [16]
Rat

  • TPTD 40 µg/kg/day 5 times a week for 6 weeks postoperative;

  • Control

  • Fusion mass volume significantly greater in TPTD group

  • Fusion rate significantly higher in TPTD group than control group (89% vs. 56%)

 Sugiura 2015 [14]
Rabbit

  • Autograft;

  • Autograft + TPTD 10µg/kg/day;

  • Low dose rhBMP-2;

  • Low dose rhBMP-2+ TPTD 10µg/kg/day

  • High dose rhBMP-2;

  • High dose rhBMP-2+ TPTD 10µg/kg/day

  • CT radiographs revealed unilateral or bilateral fusion in 50% of spines in the autograft control group, 75% of spines in the TPTD- treated group, 87.5% in both low-dose rhBMP-2–treated groups, and 100% in both high-dose rhBMP-2–treated groups

 Lina 2014 [81]
Rat

  • TPTD 30 µg/kg/day; control

  • Significantly higher fusion rate in TPTD group vs control group at 4 weeks (55.6% vs. 22.2%) and 6 weeks (88.9% vs. 55.6%)

  • Significantly higher average radiologic score in TPTD group at 4 weeks (2.03 vs. 1.45) and 6 weeks (3.66 vs. 2.56)

 Qiu 2013 [13]
Rat

  • TPTD (low dose) 4 µg/kg/day 5 days/week for 4 weeks post- op;

  • TPTD (high dose) 23 µg/kd/day 5 days/week for 4 weeks post- op;

  • Vehicle

  • Fusion rates significantly higher in high dose (68%), low dose (50%) groups than control group (20%) in a dose-dependent manner by manual palpation

  • Radiologic and micro-CT scores significantly higher in high dose and low dose groups in a dose-dependent manner

 Ming 2012 [15]
Rabbit

  • TPTD 10 µg/kg/day 8 weeks post-op;

  • Control 14 IU/animal calcitonin 8 weeks post-op

  • Histologic fusion rates significantly higher in TPTD group (86.7% vs. 50%)

  • Trend toward radiographic superiority in TPTD group (85.7% vs. 56.3%)

 Lehman 2010 [18]
Rabbit

  • TPTD 10 µg/kg/day;

  • Control

  • Fusion rate significantly higher in TPTD group than control group (81% vs. 30%)

  • Compared with control group, TPTD resulted in higher radiographic scores (4.51 vs. 3.36) and higher median mass (6.03ml vs. 3.5ml)

 O’Loughlin 2009 [17]
Rat

  • TPTD 40 µg/kg/day;

  • Control

  • Fusion rate significantly higher in TPTD group than control group (57% vs. 14%)

  • TPTD produced a larger and denser fusion mass compared to control

 Abe 2007 [12]
Rat

  • TPTD 10 µg/kg/day;

  • Control

  • Fusion rate significantly higher in TPTD group than control group

 Lawrence 2006 [11]
Osteonecrosis of Jaw (ONJ) Rat

  • ZA + DM + 0.04 mg/kg TPTD 2x/week for 3 weeks prior to tooth extraction;

  • ZA + DM + 0.04 mg/kg TPTD 2x/week for 3 weeks after tooth extraction;

  • ZA + DM+ 0.04 mg/kg TPTD 2x/week for 3 weeks after ONJ onset;

  • ZA + DM (control)

  • Pre-extraction and post-extraction TPTD groups had greater osteoclast number vs control (P = 0.037 and 0.079)

  • Inflammatory phase of bone healing more pronounced in pre- extraction TPTD group vs control (P = 0.011)

  • No significant differences in osteonecrotic area (P = 0.324) in experimental vs control groups

 Keskinruzgar 2016 [30]
Rat

  1. 0.1 mg/kg sterile saline (SS) 3x/week for 8 weeks;

  2. 0.1 mg/kg zoledronic acid (ZA) 3x/week for 8 weeks;

  3. 0.1 mg/kg ZA 3x/week for 8 weeks + molar extraction;

  4. 0.1 mg/kg ZA 3x/week for 8 weeks + molar extraction + TPTD 30 mg/kg/day for 8 weeks

  • 0% ONJ observed in groups I and II; 66% ONJ in group III (P < 0.01)

  • 22% ONJ in group IV; no significant difference vs groups I and II (P > 0.01)

  • Less inflammation in group IV vs group III, although statistically insignificant (P > 0.01)

 Dayisoylu 2013 [31]
Arthroplasty Canine

  • Proximal tibia alloy implant + TPTD 5 µg/kg daily×1 month;

  • Control

  • Bone contact non-significantly increased at implant interface in TPTD group (P = 0.07); Median shear stiffness significantly higher in TPTD group (P < 0.05)

 Daugaard 2011 [40]
Rat

  • Endosseous implant;

    Implant + TPTD 60 µg/kg, 3x/week×12 weeks;

    ZA coated implant;

    ZA coated implant + TPTD 60 µg/kg, 3x/week×12 weeks

  • TPTD+ZA treatment produced most significant increases in BV/TV, B.Ar/T.Ar, and BIC (p < 0.05)

  • TPTD+ZA significantly increased maximal push-out force, stiffness, and toughness (p < 0.05)

 Li 2013 [41]
Fracture healing Rat

  • TPTD 10 µg/kg/day;

  • Control

  • Bone mineral content, bone mineral density, and ultimate load to failure of fracture calluses were significantly increased in the TPTD- treated group compared with controls (day 28, 61, 46, and 32%; day 42, 119, 74, and 55%, respectively)

 Nakajima 2002 [54]
Rat

  • TPTD 60 µg/kg/day;

  • TPTD 200 µg/kg/day;

  • Control

  • 200 µg dose increased external callus volume after 20 days (99%) and 40 days (72%) versus control

  • 60 µg dose did not influence external callus volume after 20 days, but increased external callus volume (42%) after 40 days versus control

 Andreassen 1999 [51]
Rat

  • TPTD 5 µg/kg/day; TPTD 30 µg/kg/day;

  • Control

  • TPTD 30 µg group had significantly increased torsional strength and bone mineral density in day 21, day 35 and day 84

  • TPTD 5 µg group was associated with increased torsional strength and bone mineral density in day 35

 Alkhiary 2005 [52]
Monkey

  • TPTD 0.75 µg/kg; (Low dose)

  • TPTD 7.50 µg/kg; (High dose)

  • Control

  • Ultimate stress test and elastic modulus significantly higher in TPTD-high dose versus control

  • Callus porosity decreased dose-dependently following TPTD treatment. Mean DMB of callus was significantly higher in high dose (1.42 ± 0.30) than in control (1.09 ± 0.26) or low dose(1.13 ± 0.24)

 Manabe 2007 [53]
Rat

  • TPTD 50 mug/kg;

  • Control

  • Treatment 5 days per week

  • TPTD significantly increased callus bone mineral content and volume and trabecular bone volume/total volume (BV/TV) in open and closed fractures

  • In closed fractures, TPTD significantly increased callus size, strength, and peak torque versus control

  • TPTD did not significantly increase union rate in open fractures versus control

 Tagil 2010 [58]
Rabbit

  • 200µg rhBMP-7;

  • 200 µg rhBMP-7 + 10µg/kg/day TPTD;

  • 10µg/kg/day TPTD

  • TPTD + rhBMP-7 showed greater woven trabecular bone quantities, increased trabecular thickness, decreased trabecular separation (p < 0.04), and a trend towards increased numbers of osteoclasts (p = 0.09) ; increased torsional rigidity and compressive strength vs control and BMP-7 groups (p < 0.001)

 Morgan 2008 [55]
Rat

  • 4 µg/kg/day TPTD;

  • Five injections of 2 × 106 human mesenchymal stem cell (hMSCs);

  • 4 µg/kg/day TPTD+ five injections of 2 × 106 hMSCs

  • Significant increase in bone volume seen only in the TPTD + hMSC group

  • 8 weeks post-surgery, higher rate of complete bone bridging in TPTD + hMSC group (35%) in compared to 6.25% in TPTD alone, and 0% in control and MSC groups

 Cohn Yakubovich 2017 [56]
Rat

  • 1.5 µg/kg weekly ZA;

  • TPTD 60 µg/kg, three times a week;

  • 1.5 µg/kg weekly ZA+ TPTD 60 µg/kg, three times a week

  • ZA + TPTD showed strongest effects on BV/TV, trabecular thickness, total fluorescence-marked callus area, and biomechanical strength

 Li 2012 [57]
Rat

  • Healthy TPTD 40 µg/kg 5x/w 7-35d;

  • OVX TPTD 40 µg/kg 5x/w 7-35d;

  • OVX TPTD 40 µg/kg 5x/w 14-35d;

  • OVX TPTD 40 µg/kg 5x/w 14-28d

  • No changes in biomechanical stiffness or yield load seen in TPTD treatments 14 days post-osteotomy versus untreated healthy or OVX rats

  • In OVX rats treated with TPTD 14-28 days post-osteotomy, no increase in callus bone mineral density

  • Less pronounced enlargement in callus area for OVX rats started on TPTD treatment 14 days post-osteotomy compared to those started at 7 days

 Komrakova 2010 [59]
Non-union Rat

  • PTH 1-34 30 µg/kg/day for 2 weeks; Control in surgical model of femoral non-union

  • PTH treated group showed greater rate of bony union (50% vs 8%; P < 0.05) and lower mean gap size (1.42 vs 0.36 mm; P < 0.05) at 6 weeks post-op versus control

 Lin 2012 [60]
Stress fracture Rat

  • TPTD 40 µg/kg; alendronate 2 µg/kg; Control

  • TPTD treatment group showed significantly increased bone formation (114%) at 2 weeks, increased intracortical resorption area (23%) at 4 weeks, and enhanced ultimate force (15%) at 8 weeks versus control

 Sloan 2010 [61]

Abbreviations: TPTD: teriparatide; ZA: zoledronic acid; rhBMP: recombinant human bone morphogenetic protein; BMP-7: bone morphogenetic protein 7; DM: Dexamethasone; BIC: Bone to implant contact; ONJ: Osteonecrosis of jaw; SS: Sterile saline; OVX: Ovariectomized; hMSC: human mesenchymal stem cells; BV: bone volume; TV: total volume; AP: Anterior/Posterior; DMB: Degree of mineralization in bone; CT: Computed tomography; B.Ar: bone area; T.Ar: total area