Wnt5a deficiency in osteocalcin-expressing cells could not alleviate the osteoarthritic phenotype in a mouse model of post-traumatic osteoarthritis.

Objectives: Wnt5a, which regulates the activities of osteoblasts and osteoclasts, is reportedly overexpressed in osteoarthritis (OA) tissues. The purpose of this study was to elucidate its role in the development of OA by deleting Wnt5a in osteocalcin (OCN)-expressing cells. Materials and Methods: Knee OA was induced by anterior cruciate ligament transection (ACLT) in OCN-Cre;Wnt5afl/fl knockout (Wnt5a-cKO) mice and control littermates. Eight weeks after surgery, histological changes, cell apoptosis, and matrix metabolism of cartilage were evaluated by toluidine blue, TUNEL staining, and im-immunohistochemistry analyses, respectively. In addition, the subchondral bone microarchitecture of mice was examined by micro-computed tomography (micro-CT). Results: Histological scores show substantial cartilage degeneration occurred in ACLT knees, coupled with decreased collagen type II expression and enhanced matrix metalloproteinase 13 expression, as well as higher proportions of apoptotic cells. Micro-CT results show that ACLT resulted in decreased bone mineral density, bone volume/trabecular volume, trabecular number, and structure model index of subchondral bones in both Wnt5a-cKO and control littermates; although Wnt5a-cKO mice display lower BMD and BV/TV values, no significant difference was observed between Wnt5a-cKO and control mice for any of these values. Conclusion: Our findings indicate that Wnt5a deficiency in OCN-expressing cells could not prevent an osteoarthritic phenotype in a mouse model of post-traumatic OA.

Strontium ranelate retards disc degradation and improves endplate and bone micro-architecture in ovariectomized rats with lumbar fusion induced - Adjacent segment disc degeneration.

Objectives: Adjacent segment disc degeneration (ASDD) is one of the long-term sequelae of spinal fusion, which is more susceptible with osteoporosis. As an anti-osteoporosis drug, strontium ranelate (SR) has been reported to not only regulate bone metabolism but also cartilage matrix formation. However, it is not yet clear whether SR has a reversal or delaying effect on fusion-induced ASDD in a model of osteoporosis. Materials and methods: Fifth three-month-old female Sprague-Dawley rats that underwent L4-L5 posterolateral lumbar fusion (PLF) with spinous-process wire fixation 4 weeks after bilateral ovariectomy (OVX) surgery. Animals were administered vehicle (V) or SR (900 mg/kg/d) orally for 12 weeks post-PLF as follows: Sham+V, OVX + V, PLF + V, OVX + PLF + V, and OVX + PLF + SR. Manual palpation and X-ray were used to evaluate the state of lumbar fusion. Adjacent-segment disc was assessed by histological (VG staining and Scoring), histomorphometry (Disc Height, MVD, Calcification rate and Vascular Bud rate), immunohistochemical (Col-II, Aggrecan, MMP-13, ADAMTS-4 and Caspase-3), and mRNA analysis (Col-I, Col-II, Aggrecan, MMP-13 and ADAMTS-4). Adjacent L6 vertebrae microstructures were evaluated by microcomputed tomography. Results: Manual palpation and radiographs showed clear evidence of the fused segment's immobility. After 12 weeks of PLF surgery, a fusion-induced ASDD model was established. Low bone mass caused by ovariectomy can significantly exacerbate ASDD progression. SR exerted a protective effect on adjacent segment intervertebral disc with the underlying mechanism possibly being associated with preserving bone mass to prevent spinal instability, maintaining the functional integrity of endplate vascular microstructure, and regulating matrix metabolism in the nucleus pulposus and annulus fibrosus. Discussion: Anti-osteoporosis medication SR treatments not only maintain bone mass and prevent fractures, but early intervention could also potentially delay degenerative conditions linked to osteoporosis. Taken together, our results suggested that SR might be a promising approach for the intervention of fusion-induced ASDD with osteoporosis.

Protective effects of equol on the cartilage and subchondral bone in ovariectomized rats with osteoarthritis.

Objectives: This study aimed to determine the therapeutic effect of equol (EQ) on osteoporotic osteoarthritis (OP OA). Materials and Methods: Thirty-six 12-week-old female Sprague-Dawley rats were randomly divided into sham group, OP OA group, and EQ group (n=12). OP OA was induced by anterior cruciate ligament transection (ACLT) combined with ovariectomy (OVX). EQ was orally administrated (10 µg/g/day) after the operation for 12 weeks. The efficacy was evaluated by gross pathology and histopathologic evaluation. The underlying mechanism was investigated by immunohistochemical analysis, micro-computed tomography (micro-CT) scanning, and tartrate-resistant acid phosphatase (TRAP) staining. Results: EQ effectively retarded cartilage degeneration, decreased the levels of matrix metalloproteinases-13 (MMP-13), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), nuclear factor-kappa B P65 (NF-κB P65) and caspase-3, and increased the levels of collagen type II (Col-II), Col-I, aggrecan (AGG), and inhibitor of NF-κB α (IκBα) in the cartilage. In addition, EQ increased bone mineral density, improved the microstructural parameters of the subchondral bone (SB), and decreased the number of osteoclasts. Conclusion: EQ exerted a chondroprotective effect on OP OA in rats, associated with inhibition of the NF-κB signaling pathway and chondrocyte apoptosis. Furthermore, EQ showed an osteoprotective effect on SB via inhibiting osteoclastic activities.

The Protective Effects of Parathyroid Hormone (1-34) on Cartilage and Subchondral Bone Through Down-Regulating JAK2/STAT3 and WNT5A/ROR2 in a Collagenase-Induced Osteoarthritis Mouse Model.

OBJECTIVE: To assess the effects of PTH (1-34) on bone and cartilage metabolism in a collagenase-induced mouse model of osteoarthritis (OA) and examine whether PTH (1-34) affects the expression of JAK2/STAT3 and WNT5A/ROR2 in this process. METHODS: Eighteen 12-week-old male C57Bl/6 mice were randomly assigned into three groups as follows: sham group (Group A), the collagenase + saline injection group (Group B), and the collagenase + PTH (1-34) treatment group (Group C). Collagenase was injected (intra-articular) into the knee joint of Group B and C. The PTH (1-34)-treatment was started at 6 weeks after the operation and lasted for 6 weeks. Cartilage pathology was evaluated by gross visual, histological, and immunohistochemical assessments. Subchondral bone was evaluated by microcomputed tomography (micro-CT) and immunohistochemical analyses. RESULTS: The OARSI macroscopic and microscopic scores of Group B were higher than those of Group A (P = 0.026; P = 0.002, respectively). Group C showed statistically significant differences in macroscopic and microscopic scores from Group B (P = 0.041; P = 0.008, respectively). The results showed that the Col-II and AGG expression levels in the cartilage tissue were significantly lower in Group B than Group A (P < 0.001; P = 0.008, respectively). The Col-II and AGG expression levels were significantly higher in Group C than Group B (P = 0.009; P = 0.014, respectively). MMP-13, ADAMTS-4, Caspase-3, P53, and Bax expression levels were significantly higher in Group B than the Group A (P < 0.001; P < 0.001; P = 0.04; P < 0.001; P = 0.005, respectively); however, the cartilage tissue in Group C showed significantly less ADAMTS-4, MMP-13, Caspase-3, P53, and Bax expression than Group B (P < 0.001, P < 0.001, P = 0.044; P = 0.002; P = 0.005, respectively). Over-expressed JAK2/STAT3 and WNT5A/ROR2 were observed in both cartilage and subchondral bone in this model; however, these changes were prevented by PTH (1-34) treatment. These parameters (bone mineral density, bone volume ratio, trabecular bone pattern factor, and structure model index) of micro-CT indicated subchondral bone loss and architecture changes in Group B, but improvements in these parameters in Group C. CONCLUSIONS: PTH (1-34) exhibits protective effects on both cartilage and subchondral bone in a collagenase-induced OA mouse model, and it may be involved in down-regulating the expression of JAK2/STAT3 and WNT5A/ROR2.

Raloxifene retards the progression of adjacent segmental intervertebral disc degeneration by inhibiting apoptosis of nucleus pulposus in ovariectomized rats.

BACKGROUND: Adjacent segmental intervertebral disk degeneration (ASDD) is a major complication secondary to lumbar fusion. Although ASSD pathogenesis remains unclear, the primary cause of intervertebral disk degeneration (IVDD) development is apoptosis of nucleus pulposus (NP). Raloxifene (RAL) could delay ASDD by inhibiting NP apoptosis. METHODS: An ASDD rat model was established by ovariectomy (OVX) and posterolateral spinal fusion (PLF) on levels 4-5 of the lumbar vertebrae. Rats in the treatment groups were administered 1 mg/kg/d RAL by gavage for 12 weeks, following which, all animals were euthanized. Lumbar fusion, apoptosis, ASDD, and vertebrae micro-architecture were evaluated. RESULTS: RAL maintained intervertebral disk height (DHI), delayed vertebral osteoporosis, reduced histological score, and inhibited apoptosis. The OVX+PLF+RAL group revealed upregulated expression of aggrecan and B-cell lymphoma-2 (bcl2), as well as significantly downregulated expression of a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4), metalloproteinase-13 (MMP-13), caspase-3, BCL2-associated X (bax), and transferase dUTP nick end labeling (TUNEL) staining. Micro-computed tomography (Micro-CT) analysis revealed higher bone volume fraction (BV/TV), bone mineral density (BMD), and trabecular number (Tb.N), and lower trabecular separation (Tb.Sp) in OVX+PLF+RAL group than in the OVX+PLF group. CONCLUSIONS: RAL can postpone ASDD development in OVX rats through inhibiting extracellular matrix metabolic imbalance, NP cell apoptosis, and vertebral osteoporosis. These findings showed RAL as a potential therapeutic target for ASDD.

Denosumab alleviates intervertebral disc degeneration adjacent to lumbar fusion by inhibiting endplate osteochondral remodeling and vertebral osteoporosis in ovariectomized rats.

BACKGROUND: Although adjacent segmental intervertebral disc degeneration (ASDD) is one of the most common complications after lumbar fusion, its exact mechanism remains unclear. As an antibody to RANKL, denosumab (Dmab) effectively reduces bone resorption and stimulates bone formation, which can increase bone mineral density (BMD) and improve osteoporosis. However, it has not been confirmed whether Dmab has a reversing or retarding effect on ASDD. METHODS: Three-month-old female Sprague-Dawley rats that underwent L4-L5 posterolateral lumbar fusion (PLF) with spinous-process wire fixation 4 weeks after bilateral ovariectomy (OVX) surgery were given Dmab 4 weeks after PLF surgery (OVX+PLF+Dmab group). In addition, the following control groups were defined: Sham, OVX, PLF, and OVX+PLF (n=12 each). Next, manual palpation and X-ray were used to evaluate the state of lumbar fusion. The bone microstructure in the lumbar vertebra and endplate as well as the disc height index (DHI) of L5/6 was evaluated by microcomputed tomography (µCT). The characteristic alterations of ASDD were identified via Safranin-O green staining. Osteoclasts were detected using tartrate-resistant acid phosphatase (TRAP) staining, and the biomechanical properties of vertebrae were evaluated. Aggrecan (Agg), metalloproteinase-13 (MMP-13), and a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4) expression in the intervertebral disc were detected by immunohistochemistry and real-time polymerase chain reaction (RT-PCR) analysis. In addition, the expression of CD24 and Sox-9 was assessed by immunohistochemistry. RESULTS: Manual palpation showed clear evidence of the fused segment's immobility. Compared to the OVX+PLF group, more new bone formation was observed by X-ray examination in the OVX+PLF+Dmab group. Dmab significantly alleviated ASDD by retaining disc height index (DHI), decreasing endplate porosity, and increasing vertebral biomechanical properties and BMD. TRAP staining results showed a significantly decreased number of active osteoclasts after Dmab treatment, especially in subchondral bone and cartilaginous endplates. Moreover, the protein and mRNA expression results in discs (IVDs) showed that Dmab not only inhibited matrix degradation by decreasing MMP-13 and ADAMTS-4 but also promoted matrix synthesis by increasing Agg. Dmab maintained the number of notochord cells by increasing CD24 but reducing Sox-9. CONCLUSIONS: These results suggest that Dmab may be a novel therapeutic target for ASDD treatment.

Raloxifene inhibits the overexpression of TGF-ß1 in cartilage and regulates the metabolism of subchondral bone in rats with osteoporotic osteoarthritis.

Overexpression of transforming growth factor-beta 1 (TGF-ß1) and subchondral bone remodelling play key roles in osteoarthritis (OA). Raloxifene (RAL) reduces the serum level of TGF-ß1 in postmenopausal women. However, the effect of RAL on TGF-ß1 expression in articular cartilage is still unclear. Therefore, we aimed to investigate the protective effect of RAL on osteoporotic osteoarthritis via affecting TGF-ß1 expression in cartilage and the metabolism of subchondral bone. Osteoporotic osteoarthritis was induced by a combination of anterior cruciate transection (ACLT) and ovariectomy (OVX). Rats were divided into five groups (n = 12): The sham group, the ACLT group, the OVX group, the ACLT + OVX group, and the RAL group (ACLT + OVX + RAL, 6.25 mg/kg/day for 12 weeks). Assessment was performed by histomorphology, microcomputed tomography (micro-CT) scan, immunohistochemistry, and tartrate-resistant acid phosphatase (TRAP) staining. We found that severe cartilage degeneration was shown in the ACLT + OVX group. The histomorphological scores, the levels of TGF-ß1, and its related catabolic enzymes and osteoclasts numbers in the ACLT + OVX group were higher than those in other groups (p < 0.05). Furthermore, structure model index (SMI) and trabecular spacing (Tb.Sp) were decreased (p < 0.05), while bone mineral density (BMD), bone volume fraction (BV/TV), and trabecular number (Tb.N) were increased by RAL compared with the ACLT + OVX group (p < 0.05). Our findings demonstrated that RAL in clinical doses retards the development of osteoporotic osteoarthritis by inhibiting the overexpression of TGF-ß1 in cartilage and regulating the metabolism of subchondral bone. These results provide support for RAL in the expansion of clinical indication for prevention and treatment in postmenopausal osteoarthritis.

Parathyroid hormone (1-34) ameliorates cartilage degeneration and subchondral bone deterioration in collagenase-induced osteoarthritis model in mice.

AIMS: Parathyroid hormone (PTH) (1-34) exhibits potential in preventing degeneration in both cartilage and subchondral bone in osteoarthritis (OA) development. We assessed the effects of PTH (1-34) at different concentrations on bone and cartilage metabolism in a collagenase-induced mouse model of OA and examined whether PTH (1-34) affects the JAK2/STAT3 signalling pathway in this process. METHODS: Collagenase-induced OA was established in C57Bl/6 mice. Therapy with PTH (1-34) (10 µg/kg/day or 40 µg/kg/day) was initiated immediately after surgery and continued for six weeks. Cartilage pathology was evaluated by gross visual, histology, and immunohistochemical assessments. Cell apoptosis was analyzed by TUNEL staining. Microcomputed tomography (micro-CT) was used to evaluate the bone mass and the microarchitecture in subchondral bone. RESULTS: Enhanced matrix catabolism, increased apoptosis of chondrocytes in cartilage, and overexpressed JAK2/STAT3 and p-JAK2/p-STAT3 were observed in cartilage in this model. All of these changes were prevented by PTH (1-34) treatment, with no significant difference between the low-dose and high-dose groups. Micro-CT analysis indicated that bone mineral density (BMD), bone volume/trabecular volume (BV/TV), and trabecular thickness (Tb.Th) levels were significantly lower in the OA group than those in the Sham, PTH 10 µg, and PTH 40 µg groups, but these parameters were significantly higher in the PTH 40 µg group than in the PTH 10 µg group. CONCLUSION: Intermittent administration of PTH (1-34) exhibits protective effects on both cartilage and subchondral bone in a dose-dependent manner on the latter in a collagenase-induced OA mouse model, which may be involved in regulating the JAK2/STAT3 signalling pathway.Cite this article: Bone Joint Res 2020;9(10):675-688.

Strontium Ranelate Combined with Insulin Is as Beneficial as Insulin Alone in Treatment of Fracture Healing in Ovariectomized Diabetic Rats.

BACKGROUND Type 2 diabetes mellitus (T2DM) and estrogen deficiency both predispose fracture patients to increased risk of delayed union or nonunion. The present study investigated the effects of strontium ranelate (SR) on fracture healing in ovariectomized (OVX) diabetic rats. MATERIAL AND METHODS A mid-shaft fracture was established in female normal control (CF), diabetic (DF), and OVX diabetic (DOF) rats. Treated DOF rats received either insulin alone (DOFI) or combined with SR (DOFIS). All rats were euthanized at 2 or 3 weeks after fracture. Fracture healing was evaluated using radiological, histological, immunohistochemical, and micro-computed tomography analyses. RESULTS At 3 weeks after fracture, radiological and histological evaluations demonstrated delayed fracture healing in the DF group compared with the CF group, which was exacerbated by OVX, as indicated by the significantly lower X-ray score, BMD, BV/TV, and Md.Ar/Ps.Cl.Ar, and the markedly decreased OCN and Col I expression in the DOF group. All these changes were prevented by insulin alone or combined with SR treatment. In comparison with the DOFI group, DOFIS rats displayed markedly higher OCN expression at 2 weeks after fracture and Col I expression at 2 and 3 weeks after fracture. CONCLUSIONS These results demonstrated delayed fracture healing with preexisting estrogen deficiency and T2DM. While insulin alone and combined with SR were both effective in promoting bone fracture healing in this model, their combined treatment showed significant improvement in promoting osteogenic marker expression, but not of the radiological appearance, compared with insulin alone.

Effects of human parathyroid hormone 1-34 on bone loss and lumbar intervertebral disc degeneration in ovariectomized rats.

PURPOSE: Lumbar intervertebral disc degeneration is a common cause of lower back pain that affects the physical and mental health of patients and increases social burden. Parathyroid hormone has been reported to be effective at inhibiting disc degeneration; however, these effects have not been fully established in vivo in ovariectomized (OVX) rats. Thus, in this study, we aimed to address this issue and examine the effects of parathyroid hormone treatment in OVX rats. METHODS: Thirty female Sprague-Dawley rats, three months-old, were subjected to sham or ovariectomy surgery. Twelve weeks postsurgery, OVX rats were treated with either human parathyroid hormone [hPTH(1-34), 30 µg/kg/day] or vehicle (normal saline (NS)) treatment. The L3-6 spinal segments were harvested after 12 weeks treatment. Bone mineral density (BMD), micro-architectural parameters, and biomechanical assessment were measured at the lumbar vertebral bodies. Histology and immunohistochemistry were performed to analyze the characteristics of the lumbar intervertebral discs. RESULTS: OVX + PTH rats had significantly higher BMD, percentage bone volume density, trabecular thickness, and biomechanical strength compared with those in Sham and OVX + NS rats. Histology and immunostaining revealed that disc degeneration was not significantly different between the OVX + NS rats and the OVX + PTH rats, compared with the Sham group; the structure of nucleus pulposus was disordered, the expression of collagen I was increased, and collagen II and aggrecan were decreased. CONCLUSIONS: These findings confirmed that hPTH(1-34) treatment has substantial anabolic effects on bone mass and trabecular micro-architecture, while the excessively enhanced bone mass and strength were coupled with a non-significant effect on the disc degeneration in ovariectomized rats.

Orally administered simvastatin partially preserves lumbar vertebral bone mass but not integrity of intervertebral discs in ovariectomized rats.

The present study aimed to investigate the effect of orally administered simvastatin on lumbar vertebral bone mass and intervertebral disc (IVD) degeneration in ovariectomized (OVX) rats. A total of 30 female Sprague-Dawley (SD) rats were subjected to either bilateral ovariectomy (n=20) or sham surgery (n=10). After 12 weeks, the OVX rats were orally administered either saline vehicle (OVX + V group; n=10), or 5 mg/kg/day simvastatin (OVX + SIM group; n=10). Following 12 weeks of treatment, necropsy was conducted and bone mineral density (BMD) was determined in the L5-6 vertebrae. Furthermore, the microstructure and biomechanical properties of the L3 vertebrae were detected by micro-computed tomography and compression testing, respectively. The L5-6 vertebrae were analyzed by measurement of IVD height, observation of histological changes by van Gieson staining, and evaluation of collagen-II (col-II), aggrecan (AGG) and collagen I (col-I) expression by immunohistochemical analysis. Rats in the OVX+V group had lower BMD, bone volume/trabecular volume ratio, maximum load and elastic modulus than the sham group. Rats in the OVX + SIM group had higher BMD and biomechanical strength values than the rats in the OVX+V group. Histological analysis showed that the OVX + V and OVX + SIM groups exhibited significantly higher disc degeneration scores and significantly lower IVD height than the sham group. Immunohistochemical analysis revealed lower expression levels of col-II and AGG, but higher levels of col-I in the annulus fibrosis and endplate in OVX+V rats compared with the sham group. The OVX + SIM group exhibited levels of col-II, AGG and col-I expression comparable with those of OVX+V rats, with the exception of an upregulation of col-II expression in the annulus fibrosis. These data demonstrate that simvastatin treatment partially prevented bone loss and the deterioration of biomechanical properties of lumbar vertebrae, but not the progression of IVD degeneration in OVX rats.

Unparallel gender-specific changes in the incidence of hip fractures in Tangshan, China.

This study, which measured the incidence of hip fractures in Tangshan, China, in 2015, shows that compared to data we reported in Tangshan in 2010, the crude incidence of hip fractures in 2015 increased in females and slightly decreased in males. However, the incidences of age-specific hip fracture in females aged over 65 and males aged over 75 are both increasing. INTRODUCTION: The purpose of this study was to assess the incidence of hip fractures in 2015 in Tangshan, China, and to compare this incidence with that previously reported in Tangshan in 2010. METHODS: Data were obtained from 15 hospitals within Tangshan that had an orthopedic department, and the medical records and radiographs of all patients who sustained such fractures in 2015 were reviewed. The absolute number of admissions was described, and the incidence rates per 100,000 individuals adjusted by age (-49, 50-54, 55-59, 60-64, 65-69, 70-74, 75-79, 80-84, and ≥85 years) and gender were calculated based on the data of the Tangshan population. The 2015 population of Tangshan was determined to be 3,134,239 (1,573,118 males and 1,561,121 females). RESULTS: The population over 65 years of age represented 15.43% of the total population and included 477,021 individuals (236,140 males and 240,881 females). In 2015, there were 1645 cervical and trochanteric fractures in 714 males and 931 females, with a male-to-female ratio of 1:1.30. The overall incidence or rate of the hip fractures was 45.39 fractures per 100,000 men per year and 59.64 fractures per 100,000 women per year. Females showed a significantly higher incidence of hip fractures than males in the over 60-and-older groups, but in the youngest group, males had a markedly higher incidence than females. Compared to the incidence measured in 2010 in Tangshan, the crude incidence of hip fractures decreased by 5.04% in males and increased by 18.33% in females. The age-specific incidence increased in the male 75-and-older age groups, and the age-specific incidence increased in the female 65-and-older age groups but decreased in those younger than 65 years. CONCLUSION: Compared to the results in 2010, the crude incidence of hip fractures in 2015 in Tangshan increased in females but slightly decreased in males. However, the age-specific incidences of hip fracture in females aged over 65 and males aged over 75 are still increasing.

Strontium ranelate causes osteophytes overgrowth in a model of early phase osteoarthritis.

BACKGROUND: Osteoarthritis (OA) involves cartilage changes as well as modifications of subchondral bone and synovial tissues. Strontium ranelate (SR), an anti-osteoporosis compound, which is currently in phase III clinical trial for treatment of OA. Evidences suggest that SR preferably deposited in osteophyte, other than in subchondral bone in early phase of OA. This phenomenon raises concern about its utility for OA treatment as a disease-modifying drug. To evaluate the effect of SR on cartilage, subchondral bone mass and subchondral trabecular bone structure in medial meniscectomized (MNX) guinea pigs. METHOD: Thirty-six 3-month-old male Dunkin Hartley albino guinea pigs received either sham or medial meniscectomy operations. One week after the procedure, meniscectomized animals began 12 weeks of SR (625 mg/kg, daily) treatment by oral gavage for MNX + SR group, or normal saline for MNX + V group. All animals were euthanized 12 weeks later, cartilage degeneration and subchondral bone micro-architecture was analyzed. RESULTS: Both OARSI scores (P = 0.523 for marcoscopic scores, P = 0.297 for histological scores) and Cartilage thickness (P = 0.335) in MNX + SR group were comparable to MNX + V group. However, osteophyte sizes were larger in MNX + SR group (P = 0.014), and collapsed osteophytes in MNX + SR group (7 by 12) were significantly more than in MNX + V group (1 by 12) (P = 0.027), while immunohistochemistry indicates catabolic changes in osteophyte/plateau junction. Micro-CT analysis showed bone mineral density (BMD) (P = 0.001), bone volume fraction (BV/TV) (P = 0.008), trabecular spacing (Tb.Sp) (P = 0.020), trabecular thickness (Tb.Th) (P = 0.012) and structure model index (SMI) (P = 0.005) levels to be significantly higher in the MNX + SR group than in the MNX + V group. CONCLUSIONS: SR (625 mg/kg/day) did not protect cartilage from degeneration in MNX guinea pigs but subchondral bone was significantly enhanced. In early phase OA, SR administration causes osteophyte overgrowth, which may be related to incorporation into mineralizing osteophytes. This adverse effect is important for future studies of SR in OA.

Are estrogen-related drugs new alternatives for the management of osteoarthritis?

Osteoarthritis (OA) is a chronic degenerative disease involving multiple physiopathological mechanisms. The increased prevalence of OA after menopause and the presence of estrogen receptors in joint tissues suggest that estrogen could help prevent development of OA. This review summarizes OA research with a focus on the effects of estrogen and selective estrogen receptor modulators (SERMs). Preclinical studies and clinical trials of estrogen therapy have reported inconsistent results. However, almost all studies assessing SERM treatment have obtained more consistent and favorable effects in OA with a relatively safety and tolerability profiles. At present, some SERMs including raloxifene and bazedoxifene have been approved for the treatment of osteoporosis. In summary, estrogen-related agents may exert both a direct effect on subchondral bone and direct and/or indirect effects upon the surrounding tissues, including the articular cartilage, synovium, and muscle, to name a few. Estrogen and SERMs may be particularly favorable for postmenopausal patients with early-stage OA or osteoporotic OA, a phenotype defined by reduced bone mineral density related to high remodeling in subchondral bone. At present, no single drug exists that can prevent OA progression. Although estrogen-related drugs provide insight into the continued work in the field of OA drug administration, further research is required before SERMs can become therapeutic alternatives for OA treatment.

Enhancement of Lumbar Fusion and Alleviation of Adjacent Segment Disc Degeneration by Intermittent PTH(1-34) in Ovariectomized Rats.

Osteoporosis, which is prevalent in postmenopausal or aged populations, is thought to be a contributing factor to adjacent segment disc degeneration (ASDD), and the incidence and extent of ASDD may be augmented by osteopenia. Parathyroid hormone (PTH) (1-34) has already been shown to be beneficial in osteoporosis, lumbar fusion and matrix homeostasis of intervertebral discs. However, whether PTH(1-34) has a reversing or retarding effect on ASDD in osteopenia has not been confirmed. In the present study, we evaluated the effects of intermittent PTH(1-34) on ASDD in an ovariectomized (OVX) rat model. One hundred 3-month-old female Sprague-Dawley rats underwent L4 -L5 posterolateral lumbar fusion (PLF) with spinous-process wire fixation 4 weeks after OVX surgery. Control groups were established accordingly. PTH(1-34) was intermittently administered immediately after PLF surgery and lasted for 8 weeks using the following groups (n = 20) (V = vehicle): Sham+V, OVX+V, Sham+PLF+V, OVX+PLF+V, OVX+PLF+PTH. The fused segments showed clear evidence of eliminated motion on the fusion-segment based on manual palpation. Greater new bone formation in histology was observed in PTH-treated animals compared to the control group. The extent of ASDD was significantly increased by ovariotomy. Intermittent PTH(1-34) significantly alleviated ASDD by preserving disc height, microvessel density, relative area of vascular buds, endplate thickness and the relative area of endplate calcification. Moreover, protein expression results showed that PTH(1-34) not only inhibited matrix degradation by decreasing MMP-13, ADAMTS-4 and Col-I, but also promote matrix synthesis by increasing Col-II and Aggrecan. In conclusion, PTH(1-34), which effectively improves lumbar fusion and alleviates ASDD in ovariectomized rats, may be a potential candidate to ameliorate the prognosis of lumbar fusion in osteopenia.

Protective effect of calcitonin on lumbar fusion-induced adjacent-segment disc degeneration in ovariectomized rat.

BACKGROUND: Intervertebral disc (IVD) degeneration and pathological changes in the spinal cord are major causes of back pain. In addition to its well-established anti-resorptive effect on bone, calcitonin (CT) potentially exerts protective effects on IVD degeneration in ovariectomized rats. However, possible therapeutic effects of CT on lumbar fusion-induced adjacent-segment disc degeneration (ASDD) have not been investigated yet. In this study, we examined the effects of CT on IVD degeneration adjacent to a lumbar fusion in ovariectomized rats. METHODS: Posterolateral lumbar fusion (PLF) at L4-5 was performed 4 weeks after ovariectomy (OVX) or sham surgery in female Sprague-Dawley rats. Following PLF + OVX, rats received either salmon CT (OVX + PLF + sCT, 16 IU/Kg/2d) or vehicle (OVX + PLF + V) treatment for 12 weeks; the remaining rats were divided into Sham + V, OVX + V, and PLF + V groups. Fusion status was analyzed by manual palpation and radiography. Adjacent segment disc was assessed by histological, histomorphometric, immunohistochemical analysis. L6 vertebrae microstructures were evaluated by micro-computed tomography. RESULTS: Histological analysis showed more severe ASDD occurred in OVX + PLF + V rats compared with the OVX + V or PLF + V groups. CT treatment suppressed the score for ASDD, increased disc height, and decreased the area of endplate calcification. Immunohistochemical staining demonstrated that CT decreased the expression of collagen type-I, matrix metalloproteinase-13, and a disintegrin and metalloproteinase with thrombospondin motifs-4, whereas it increased the expression of collagen type-II and aggrecan in the disc. Micro-computed tomography indicated that CT increased bone mass and improved the microstructure of the L6 vertebrae. CONCLUSIONS: These results suggest that CT can prevent ASDD, induce beneficial changes in IVD metabolism, and inhibit deterioration of the trabecular microarchitecture of vertebrae in osteoporotic rats with lumbar fusion.

Alendronate Prevents Intervertebral Disc Degeneration Adjacent to a Lumbar Fusion in Ovariectomized Rats.

STUDY DESIGN: A model of disc degeneration adjacent to a lumbar fusion in osteoporotic rats. OBJECTIVE: We determined the effect of alendronate (ALN) on the disc degeneration adjacent to a lumbar fusion in ovariectomized rats. SUMMARY OF BACKGROUND DATA: Adjacent-segment disc degeneration (ASDD) is one of the negative sequelae of spinal fusion. Previous studies have shown that ALN can alleviate disc degeneration. However, no data have been documented regarding the effect of ALN on ASDD after posterolateral lumbar fusion (PLF) in osteoporosis. METHODS: 50 female Sprague-Dawley rats underwent either a sham operation (sham) (n = 20) or bilateral ovariectomy (OVX) (n = 30). 4 weeks later, all but 10 rats from each group underwent PLF consisting of an intertransverse process spinal fusion using autologous-iliac-bone grafts with spinous-process wire fixation at the L4-L5 segment. Animals were subcutaneously administered vehicle (V) or ALN (70 µg/kg/wk) for 12 weeks post-PLF as follows: Sham+V, OVX+V, PLF+V, OVX+PLF+V, and OVX+PLF+ALN. Fusion status was analyzed by manual palpation and radiography. Adjacent-segment disc was assessed by histological, histomorphometric, immunohistochemical, and mRNA analysis. L6 vertebrae microstructures were evaluated by microcomputed tomography. RESULTS: The fused segments showed clear evidence of fusion based on manual palpation and radiographs. The OVX+PLF+V group showed more severe degenerative alterations and higher histological scores in the disc than the Sham+V, OVX+V, and PLF+V groups (P < 0.05). Compared with the OVX+PLF+V group, the OVX+PLF+ALN group exhibited significantly improved bone mass and vertebrae microstructures (P < 0.05), an increased disc height, and a decreased endplate calcification area (P < 0.05). ALN also significantly decreased Col-I, MMP-13, and ADAMTS-4 expression and increased Col-II and Aggrecan expression in the disc matrix (P < 0.05). CONCLUSION: ALN effectively alleviated ASDD post-PLF in ovariectomized rats. These data indicate that ALN can be used as a potential therapeutic agent to attenuate ASDD progression in osteoporosis.

Age dependent changes in cartilage matrix, subchondral bone mass, and estradiol levels in blood serum, in naturally occurring osteoarthritis in Guinea pigs.

The Dunkin Hartley (DH) guinea pig is a widely used naturally occurring osteoarthritis model. The aim of this study was to provide detailed evidence of age-related changes in articular cartilage, subchondral bone mineral density, and estradiol levels. We studied the female Dunkin Hartley guinea pigs at 1, 3, 6, 9, and 12 months of age (eight animals in each group). Histological analysis were used to identify degenerative cartilage and electron microscopy was performed to further observe the ultrastructure. Estradiol expression levels in serum were assessed, and matrix metalloproteinase 3 and glycosaminoglycan expression in cartilage was performed by immunohistochemistry. Bone mineral density of the tibia subchondral bone was measured using dual X-ray absorptiometry. Histological analysis showed that the degeneration of articular cartilage grew more severe with increasing age starting at 3 months, coupled with the loss of normal cells and an increase in degenerated cells. Serum estradiol levels increased with age from 1 to 6 months and thereafter remained stable from 6 to 12 months. Matrix metalloproteinase 3 expression in cartilage increased with age, but no significant difference was found in glycosaminoglycan expression between 1- and 3-month old animals. The bone mineral density of the tibia subchondral bone increased with age before reaching a stable value at 9 months of age. Age-related articular cartilage degeneration occurred in Dunkin Hartley guinea pigs beginning at 3 months of age, while no directly positive or negative correlation between osteoarthritis progression and estradiol serum level or subchondral bone mineral density was discovered.

An increase in the incidence of hip fractures in Tangshan, China.

UNLABELLED: We determined the number and incidence of hip fractures in Tangshan, China, in 2010. Compared with data we reported in Tangshan from 1994, the crude and age-specific incidence increased significantly for both sexes, especially in women. Strategies are needed for effective fracture prevention in the future. INTRODUCTION: The aims of the study were to determine the incidence of cervical and trochanteric fractures of the proximal femur in Tangshan, China, in 2010 and to compare the incidence with data from 1994. METHODS: The orthopedic departments of 15 hospitals in Tangshan were visited in 2010; the medical records and radiographs of patients who had sustained cervical and trochanteric fractures were reviewed. The absolute number of admissions was collated and the incidence rate per 100,000 person years was calculated, adjusted by different age ranges, and gender. We then calculated the age-standardized incidence in 2010 as compared with those from 1994. RESULTS: The population of Tangshan in 2010 was determined to be 3,075,382 (1,558,173 males; 1,517,209 females); there were 1,509 cervical and trochanteric fractures (in 745 males and 764 females). The overall incidence was 47.8 and 50.4 fractures per 100,000 per year for men and women, respectively. Females showed a higher fracture incidence than males in those aged 55 years and over. Comparing the 2010 data with the 1994 findings, the incidence increased by 85% in men and by 306% in women; age-specific increases were observed in all female and male groups (except the 55-59 years age group). CONCLUSIONS: Compared with the results in 1994, the incidence of hip fracture has markedly increased in 2010 in Tangshan, China. It is necessary to implement a comprehensive policy for hip fracture prevention in our communities.