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Table 1 Characteristics of included preclinical studies

From: Bisphosphonates as disease-modifying drugs in osteoarthritis preclinical studies: a systematic review from 2000 to 2020

References Animal model (n) OA model and site Therapy: dosage, frequency and duration Start point * Follow-up and evaluations Main results
She et al. [20] New Zealand Rabbit; Male
5–7 monthsold
(32)
Surgically-induced OA: ACLT
Knee
Zoledronic acid (250, 50 and 10 μg/kg i.v.) Once post-surgery 0 days 0, 4, and 8 weeks
X-ray absorptiometry scanner (BMD) and MRI (cartilage thickness). Histology of cartilage (Mankin score system)
ZOL improved the microstructure and reduced the degeneration of articular cartilage in a dose-dependent manner, showing better chondroprotective effects at the high doses. On subchondral bone, ZOL ↑BMD.
Lampropoulou-Adamidou et al. [21] New Zealand Rabbit; Male
25 weeksold
(18)
Surgically induced OA: ACLT
Knee
Zoledronic acid (0.6 mg/kg i.v.) On day 1, 15, and 29 1 day 8 weeks
Macroscopic evaluation Histology of cartilage (modified Mankin score)
Macroscopically ZOL group had significantly milder ulcerations, cartilage softening and fibrillation. Microscopically ZOL showed chondroprotective effect.
Permuy et al. [22] New Zealand Rabbit; Female
6–7 months old
(32)
Surgically induced OA: ACLT and partial MMT.
Knee
Glucosamine (21.5 mg/kg/day oral) +/or Risedronate (0.07 mg/kg/day oral) 8 weeks 3 weeks 11 weeks
Histology of cartilage and synovial (OARSI score). Histomorphometric evaluation and μ-CT (BV/TV, Tb.Th, Tb.Sp, Tb.N, Tb.Pf)
RIS treatment alone or in combination showed improves cartilage swelling, superficial fibrillation and less inflammatory changes in the synovial membrane. On subchondral bone, RIS modify the orientation of trabecular lattice (↓Tb.Sp and ↑Tb.N)
Shirai et al. [23] New Zealand Rabbit; Female
9 months old
(30)
Surgically induced OA: ACLT
Knee
Alendronate (0.14 mg/kg/weekly s.c.) 2, 4 or 12 weeks 0 days 2, 4, or 12 weeks
Histology of cartilage (Mankin score system) μ-CT (BV/TV), subchondral bone plate thickness and osteophyte development. Immunohistochemistry (MMP13, IL-1β, COLX, VEGF and RANKL)
ALN showed chondroprotective effect and prevented periarticular bone loss. Immunohistochemical analysis showed that ALN suppressed the expression of MMP13, IL-1β, COLX, VEGF, and RANKL in OA cartilage.
Zhang et al. [24] Japanese Rabbit; Male
10 weeks old
(30)
Surgically-induced OA: ACLT
Knee
Alendronate (10 μg/kg/day s.c.) 56 days 4 days 60 days
Histology of cartilage (Mankin score system) X-ray absorptiometry scanner (BMD) and histomorphometric assays (BV/TV, Tb.Th, Tb.N, Tb.Sp). Immunohistochemistry (BMP-2 and MMP-13)
ALN treatment reduced cartilage lesions and delayed the cartilage degeneration. Significantly suppressed subchondral bone resorption (↑BMD, BV/TV, Tb.Th, and Tb.N). Also, showed chondroprotective role in immunohistochemistry assays (↑BMP-2 and (↓MMP-13).
MacNeil et al. [25] New Zealand Rabbit; Female
Mature
(18)
Surgically-induced OA: ACLT
Knee
Risedronate (0.01 mg/kg/day s.c.) 6 weeks ? 6 weeks
μ-CT (BV/TV, BS/BV, Tb.N, Tb.Th, Tb.Sp, Conn.D, Ct.Th, BMD)
RIS group exhibited areas of developing osteophytes. Cartilage surface showed only focal roughening. RIS animals showed periarticular bone conservation (BV/TV, Ct.Th)
Doschak et al. [26] New Zealand Rabbit
1 year old (28)
Surgically-induced OA: ACLT
Knee
Risedronate (0.01 mg/kg/daily s.c.) 6 weeks ? 6 or 14 weeks
Histology of cartilage (Modified Mankin score system) μ-CT (laxity and volume of the MCL)
RIS treatment conserved periarticular bone and improved MCL-complex laxity. However, showed the higher scores on the modified Mankin scale.
Doschack et al. [27] New Zealand Rabbit
1 year old
(30)
Surgically induced OA: ACLT
Knee
Risedronate (0,01 mg/kg/daily s.c.) 6 weeks ? 6 weeks
Histology of cartilage (Modified Mankin score system). X-ray absorptiometry scanner (BMD)
Biochemical of periarticular bone
RIS treatment conserved periarticular BMD and ligament mechanical porperties. RIS did not have de capacity to supress osteophytosis nor early cartilage signs of degradation.
Muehleman et al. [28] New Zealand Rabbit; Male
Adolescent
(58)
Chemically induced OA: Chymopapain
Knee
Zoledronic acid (10 μg/kg/3 times per week s.c.) 8, 28, or 56 days 1 day 28 or 56 days
Macroscopic evaluation
Histology of cartilage and PG content
Urine samples (collagen cross-links)
ZOL treated animals displayed a significantly lower degree of grossly and histologically cartilage degeneration. Urinary levels of collagen cross-links were higher in untreated animals.
Cinar et al. [29] Wistar Rat
Male
Adult
(48)
Surgically induced OA: ACLT
Knee
Zoledronic acid (10 μg/kg/weekly intra-articular) 4 days, 3 or 6 weeks 0 days 4 day, 3 weeks, or 6 weeks
Histology score of cartilage (Mankin score system) and synovial
Serum analyses (COMP)
ZOL intra-articular administration showed significant reduced synovitis and partially chondroprotective effect, although did not completely prevent cartilage damage.
Bagi et al. [30] Lewis Rat
Male
4 month old
(48)
Surgically induced OA: MM
Knee
Zoledronic acid (100 μg/kg/2 times per week s.c.) PTH (40 μg/kg/5 times per week s.c.) 10 weeks 0 days 5 and 10 weeks
Histological score (OARSI adapted scale) μ-CT (BV/TV, BS/BV, Tb.N, Tb.Th, Tb.Sp)
Serum analyses (Osteocalcin, P1NP, CTX-1, CTX-II)
ZOL and PTH improved subchondral bone mas (↑BV/TV, TB.N and Tb.Th), but both treatments failed to prevent or correct cartilage deterioration, thickening of the subchondral bone plate, osteophyte formation nor the mechanical incapacity. ZOL ↓CTX-II level serum.
Zhu et al. [31] Sprague-Dawley Rat; Female
7 months-old (78)
Spontaneusly model: Menopause-OA (OVX)
Knee
Alendronate (30 μg/kg/twice weekly s.c.) 2, 10 or 18 weeks 0 or 8 weeks 2, 10, or 18 weeks
Histology of cartilage (Mankin score system) μ-CT (BV/TV, Tb.Th, Tb.N, Tb.Sp)
Urinary CTX-I and serum CTX-II. Inmunohistochemistry (MMP-9, MMP-13)
Early ALN treatment prevented both subchondral bone loss and cartilage surface erosion. Late ALN treatment was able to inhibit subchondral bone loss but did not reverse cartilage erosion. ALN ↓MMP-13 and MMP-9.
Mohan et al.
[32]
Wistar Rat
Male
8 weeks-old
(84)
Chemically induced OA: MIA
Knee
Alendronate (15 μg/kg/2 times per week s.c.) Pre-emptive: day 0 to 14; early: day 14 to 42; delayed: day 42 to end of week 10 0, 14, or 42 days 2, 6 and 10 weeks
Histology score (OARSI scoring system) μ-CT (BV, BV/TV, Tb.Th, Tb.Sp, and Tb.N)
Serum analyses (COMP, CTX-I) and urine CTX-II
Pre-emptive ALN treatment preserved subchondral bone, decreased bone turnover and had moderate effects on cartilage degradation.
Early and delayed ALN treatments prevented bone loss and decreased bone turnover, but had no significant effect on cartilage degradation.
Panahafir et al.
[33]
Sprague-Dawley Rat; Female
6 weeks-old
(15)
Surgically induced OA: MMT
Knee
Alendronate (0.12 mg/kg/twice weekly s.c.) 8 weeks 1 day 0, 4, and 8 weeks
Histologic assessments of cartilage (Modified Mankin score system) μ-CT (BMD and BV of osteophytes)
ALN treatment inhibited osteophyte development and were more cartilaginous (↓BMD). Also, ALN showed reduced degeneration of the cartilage.
Koh et al. [34] Sprague-Dawley Rat; Female
6 months-old
(30)
Chemically induced OA: MIA
Knee
Pamidronate (3 mg/kg/weekly s.c.) 8 weeks 8 weeks earlier 8 weeks after induced OA
Macroscopic evaluation (ICRS grading system) μ-CT (BV/TV, Tb.N, Tb.Th, Tb.Sp, Tb.Pf, SMI)
PAM treatment showed less trabecular bone changes and cartilage damage
Jones et al. [35] Sprague-Dawley Rat; Female
6 weeks old
(58)
Surgically induced OA: KTI
Knee
Alendronate (0.12 mg/kg/2 times per week s.c.)
Risedronate (0.06 mg/kg/2 times per week s.c.)
1 day 1 day, 4 and 8 weeks
Histologic assessments (Modified Mankin scoring system on toluidine blue and safranin-O stained samples)
MRI and μ-CT (BV and osteophyte formation)
Treatments with BPs showed reduced levels of trabecular bone loss (↑BV). ALN reduced bony osteophyte development, but RIS did not positively impact. Histologic analysis confirmed the chondroprotective effect of both BPs.
Strassle et al. [36] Sprague-Dawley Rat; Male
8 weeks-old
(195)
Chemically induced OA: MIA
Knee
Zoledronic acid (10, 30, or 100 μg/kg/every third day s.c.) Pre-emptive: day 1 to 21; early: day 14 to 21 or 35; delayed chronic: day 21 to 35; sub-chronic: 28 to 35 1, 14, 21, or 28 days 5 or 22 days
X-ray absorptiometry scanner (BMD)
Histological analysis (toluidine blue and TRAP stained samples)
Pre-emptive ZOL treatment ↑BMD and prevented the thinning of the cartilage, loss of proteoglycan and chondrocytes. Also, cartilage and subchondral bone resorption. In advanced OA, ZOL partially restored BMD.
Hayami et al. [37] Sprague-Dawley Rat; Male
20 weeks-old
(95)
Surgically induced OA: ACLT
Knee
Alendronate (15 or 120 μg/kg/2 times per week s.c.) 2 or 10 weeks 3 days 2 or 10 weeks
Macroscopic evaluation and histological analysis (Modified Mankin score system)
Histomorphometric assays: subchondral bone volume (BV/TV) and osteophytes. Serum and urinary analyses (COMP, CTX-I, CTX-II) Inmunohistochemistry (MMP-13, MMP-9, TGFβ)
ALN showed chondroprotective effect, suppressed subchondral bone resorption and reduced osteophyte area (dose-dependent manner). ↓MMP-13, MMP-9 and TGFβ.
Adebayo et al. [38] C57BL/6 (B6) and FVB/NJ (FVB) Mice
Male
26 week old
Non-invasive loading OA: CACTC
Knee
Alendronate (26 μg/kg/day i.p.) 1, 2 or 6 weeks 0 days 1, 2, or 6 weeks
Histology of cartilage and osteophyte (Modified OARSI scoring system)μ-CT (BV/TV, Tb.Th, Tb.Sp)
ALN treatment inhibited bone remodeling and, in B6 mice cartilage pathology was exacerbated, while in FVB mice cartilage loss was protected. ALN inhibited osteophyte maturation, but did not affect osteophyte size.
Khorasani et al. [39] C57BL/6 N Mice
Female
10 weeks old
(90)
Non-invasive loading OA: Tibial compression overload
Knee
Alendronate (40 or 100 μg/kg/twice weekly s.c.) 7, 14 or 56 days 0 days 7, 14 or 56 days
Histologic assessments (OARSI score system) μ-CT (BV/TV, Tb.Th, BMD, Ct.Th, and osteophyte volume)
Serum analyses (CTX-I and P1NP)
High-dose ALN of treatment was able to prevent early trabecular bone loss and cartilage degeneration, but was not able to inhibit osteophyte formation, nor was it able to mitigate long-term degeneration. ALN ↓CTX-I serum
Sniekers et al. [40] C3H/HeJ Mice
Female
12 weeks old
(32)
Menopause-related OA (OVX) and chemically-induced OA: MIA
Knee
Estradiol (12 μg/day s.c. implant)
Alendronate (2 mg/kg/weekly i.p.)
12 weeks
0 days 12 weeks
Histology of cartilage and osteophyte (OARSI score system) μ-CT (Subchondral cortical thickness, BV/TV, osteophytosis)
ALN ↑subchondral cortical bone thickness and BV/TV and tended to diminish cartilage damage.
Thomsen et al. [41] Dunkin Hartley Guinea Pig
Male
3 months old
(56)
Spontaneusly model: Naturally occurring
Knee
Risedronate (30 μg/kg/five times a week s.c.) 6, 12, or 24 weeks 0, 6, 12, or 24 weeks
Histologic assessments (OARSI score) and histomorphometry. Indentation mechanical testing (subchondral bone plate stiffness). Serum CTX-II
RIS did not reduce the articular cartilage damage and did not influence on subchondral bone plate stiffness, but ↓ serum CTX-II. RIS treatment reduced bone resorption and bone formation.
Ding et al. [42] Dunkin Hartley Guinea Pig
Male
6.5 months old
(66)
Spontaneusly model: Naturally occurring
Knee
Alendronate (10 or 50 μg/kg/twice weekly s.c.) 9 or 17 weeks 9 or 17 weeks
Histology score of cartilage (Mankin scoring system on safranin-O samples-CT (Subchondral bone plate thickness, Tb.Th, Tb.Sp, and BS/BV) Bone density and mineral
ALN groups showed worse cartilage degeneration in spite of subchondral bone plate thickness, bone mineral content and density.
Dearmin et al. [43] Mixed-breed Dog; Male
11–24 months old
(24)
Surgically induced OA: ACLT
Knee
Zoledronic acid (10 or 25 μg/kg/every 3 months s.c.) 12 months 1 day 0, 1, 6, 9, and 12 months
Serum, synovial and radiographic analysis (BAP, type I and II collagen, CS846)
Gross articular analyses of cartilage, meniscus and osteophyte lesions
ZOL high-dose group resulted in a chondroprotective effect with lower articular defects but did not have the capacity to prevent osteophytosis nor the progression of the radiographic lesions. In synovial fluid, ZOL ↓type I and II collagen.
Pelletier et al. [44] Crossbred dog
-
1–4 years old
(31)
Surgically induced OA: ACLT
Knee
Tiludronic acid (2 mg/kg on days 14, 28, 56 and 84 s.c.) + extracapsular stabilization surgery 14 days 1 year
Macroscopic evaluation and histological assessments of cartilage and synovial (Modified Sakakibara scale). MRI and cartilage volume
PCR (ADAMTS-4 and 5, MMP-1, MMP-3, MMP-13, BMP-2, IGF-1, and TGF-β1)
TLN-treated animals presented a reduction in the severity of macroscopic and histologic cartilage lesions and showed ↓MMP-1, MMP-3, and MMP-13 levels.
Moreau et al. [45] Crossbred dog
-
2–3 years old
(16)
Surgically induced OA: ACLT
Knee
Tiludronate (2 mg/kg/every two weeks s.c.) 6 weeks 0 days 8 weeks
Macroscopic and histological grading of cartilage and synovial (OARSI scoring system)
Histomorphometry (cCg.Th, SB.Th, Tb.Th, and Tb.S). Synovial fluid and inmunohistochemistry (PGE2, NOX, MMP-1, MMP-13, cathepsin K, and ADAMTS-5)
TLN treated animals having less joint effusion, lower synovitis score and a greater subchondral bone surface. ↓PGE2, NOX, MMP-13, cathepsin K and ADAMTS5. TLN failed to prevent or correct cartilage lesion and osteophyte development.
  1. ACLT anterior cruciate ligament transection, ADAMTS a disintegrin and metalloproteinase with thrombospondin motifs, ALN Alendronate, BMD bone mineral density, BAP bone-specific alkaline phosphatase, BPs bisphosphonates, BMP bone morphogenic protein, BS/BV bone surface to bone volume ratio, BV/TV bone volume fraction, CACTC cyclic articular cartilage tibial compression, cCg.Th calcified cartilage thickness, COLX type-X collagen, Conn.D connectivity density, COMP cartilage oligomeric matrix protein, CS846 chondroitin sulfate 846, μ-CT micro-computed tomography, Ct.Th cortical thickness, CTX collagen carboxyterminal telopeptide, IGF insulin-like growth factor, IL interleukin, MCL medial collateral ligament, KTI knee triad injury, MIA monosodium iodoacetate, MMP matrix metalloproteinase, MMT medial meniscectomy, MRI magnetic resonance imaging, NOx nitrites and nitrates, PCR polymerase chain reaction, OA osteoarthritis, OARSI Osteoarthritis Research Society International, OVX ovariectomized, PAM pamidronate, PG prostaglandin, P1NP procollagen type 1 N-terminal propeptide, RANKL receptor activator of nuclear factor-kappa B ligand, RIS risedronate, SB.Th subchondral bone thickness, SMI structural model index, Tb.N trabecular number, Tb.Pf trabecular bone pattern factor, Tb.S trabecular separation, Tb.Th trabecular thickness, TGF transforming growth factor, TRAP tartrate-resistant acid phosphatase, ZLN zoledronic acid, VEGF vascular endothelial growth factor, TLN tiludronate. *Start point: time between induced OA and treatment administration