Elsevier

Bone

Volume 53, Issue 2, April 2013, Pages 340-349
Bone

Original Full Length Article
Alendronate protects against articular cartilage erosion by inhibiting subchondral bone loss in ovariectomized rats

https://doi.org/10.1016/j.bone.2012.12.044Get rights and content

Abstract

Osteoporosis (OP) and osteoarthritis (OA) are major health problems in the increasing elderly population, particularly in postmenopausal women, but their relationship remains unclear. The present study investigated whether alendronate (ALN), a potent inhibitor of bone resorption, could protect articular cartilage from degeneration in a combined animal model of OP and OA induced by ovariectomy (OVX). Seventy-eight seven-month-old female Sprague–Dawley rats were assigned into five experimental groups: (1) sham-operated with vehicle treatment, (2) sham-operated with ALN treatment, (3) OVX with vehicle treatment, (4) ALN treatment starting at OVX, and (5) ALN treatment starting at eight weeks after OVX. Histological and micro-CT analyses, together with urine collagen degradation markers, indicated that early ALN treatment completely prevented both subchondral bone loss and cartilage surface erosion induced by OVX. Although late ALN treatment also inhibited subchondral bone loss and significantly reduced cartilage erosion in the OVX rats, these tissues did not completely recover even after 10-weeks of ALN treatment. Quantitative RT-PCR analyses showed that the protective effect of ALN correlated with increased ratio of OPG/RANKL in both subchondral bone and cartilage. Moreover, whereas OVX caused upregulation of expression of matrix metalloproteinases MMP-13 and MMP-9 in the articular cartilage and chondrocytes in the interface between the articular cartilage and subchondral bone, respectively, early ALN treatment blocked whereas late ALN treatment attenuated the upregulation of these catabolic enzymes in the corresponding tissues. Together, these data indicate that the subchondral bone loss plays an important role in OA pathogenesis in the combined OP and OA model and suggest that treatment timing is an important factor for the effectiveness of anti-resorptive drug therapy of combined OP and OA.

Highlights

► Osteoporosis and osteoarthritis are major health problems in the elderly population, particularly in postmenopausal women, but their relationship remains unclear. ► Early ALN treatment completely prevented both subchondral bone loss and cartilage surface erosion caused by OVX. ► Late ALN treatment inhibited subchondral bone loss and significantly reduced cartilage erosion, although they did not recover to normal levels. ► Treatment for OP with bone resorption inhibitors reduces cartilage degeneration when menopause-related OP and OA coexist in same individuals.

Introduction

Osteoarthritis (OA) is characterized by gradual and uneven loss of articular cartilage, osteophyte formation, subchondral sclerosis and degeneration of periarticular structures [1], [2], [3]. This disease is usually classified into primary or secondary OA, with secondary OA with injury or other predisposing factors. The prevalence of primary OA increases with age in both men and women, and the incidence in women increases dramatically after menopause. Multiple studies in various ovariectomized (OVX) animal models as well as epidemiological findings of chondroprotective effects of hormone replacement therapy strongly suggest the involvement of estrogen deficiency in post-menopausal OA [4], [5], [6].

Also prevalent in the elderly, especially elderly women, is osteoporosis (OP), a systemic skeletal disorder characterized by a compromised bone strength and high susceptibility to bone fractures [7], [8]. In contrast to OA, which has traditionally been regarded primarily as a cartilage disorder with recent studies suggesting involvement of subchondral bone alterations in its pathogenesis, OP is caused by increased bone loss. Recent studies in both animal models and humans suggest that systemic OP may have a role in OA pathogenesis [9], [10]. However, experimental investigations addressing the relationship between OA and OP are limited and the relationship between the two diseases remains unclear [11].

Alteration in subchondral bone may lead to changes in load distribution, which may in turn cause or accelerate cartilage damage in OA [12], [13], [14], [15], [16]. OP can also result in a reduced bone mineral density (BMD) in the subchondral bone. These observations raised a possibility that the subchondral bone might play an important role during the interplay between OP and OA. Recent animal study showed that prior induction of OP increased the severity of cartilage damage in experimental OA induced by anterior cruciate section and partial medial meniscectomy in rabbits, and BMD changes in subchondral knee bone also showed a trend to correlate inversely with cartilage damage [9], [10]. However, previous studies mainly focus on secondary OA caused by trauma. The result from the post-traumatic OA may not be applied to the primary OA, particularly in menopause-related OA, as the subchondral bone plays a different role in the different subgroups of OA [1]. In addition, although supplementation of estrogen is able to protect cartilage from degeneration, estrogen is known to have dual effects on both cartilage and bone [4], [5], [6] and it is, therefore, still uncertain whether the acceleration of OA by OP is the result of estrogen insufficiency or abnormal subchondral bone.

Alendronate (ALN) is a nitrogen-containing bisphosphonate and a potent inhibitor of bone loss. At present, ALN has been used clinically for the treatment of OP [17], [18]. It has been reported that ALN was chondroprotective in a rat anterior crusiate ligament transaction (ACLT) model of OA [14], [19]. ALN treatment also decreased spinal osteophyte progress and disk space narrowing in humans [20]. In addition, Carbone et al. reported that ALN treatment decreased pain severity in an elderly population with knee OA [21]. However, whether ALN is able to counteract degeneration of articular cartilage in the presence of OP has not been investigated. In addition, whereas previous studies showed that early or late treatment with bisphosphonate produced different therapeutic effects on OP, the effects of treatment timing on OP and OA remains unknown.

Animal models experiencing both OP and OA have become valuable tools for investigating the relationship between these two diseases. Surgical induction is a common method used in various animal models of degenerative joint lesions [14], [19], [22], [23]. However, surgically induced joint damage resembles those observed in post-traumatic OA more than the spontaneously evolving forms such as menopause-related OA. Ovariectomized (OVX) rats are commonly used OP model to mimic the post-menopausal bone loss [24], [25], [26]. Recent studies showed that older ovariectomized rats (i.e. 5 months of age or more) could be used as an in vivo model for nontraumatic postmenopausal OA [27], [28], [29]. In the present study, we hypothesized that progression of OA-like cartilage erosion could be inhibited by the early or late treatment for subchondral bone loss when menopause-related OP and OA coexist in same individuals. To test this, the protective effects of early and late treatment of ALN on articular cartilage and subchondral bone were investigated in OVX rats. Moreover, several bone microstructural parameters and metabolic modulators that are involved in cartilage and subchondral bone remodeling were also investigated.

Section snippets

Animals and study design

Seventy-eight 7-months-old female Sprague–Dawley rats were used in this study. Bilateral OVX were performed to induce a combined model of OP and OA as described previously [27], [28], [29]. Animals were housed 2–3 per cage at 25 °C with a 12-h light/12-h dark cycle and given food and water ad libitum. The body weight of the animals was recorded at regular intervals. All experiments were approved by the Animal Ethics Committee of Sichuan University, and were performed according to Guidelines for

Results

The treatments were well tolerated by the animals. In comparison with sham-operated animals, the OVX animals had gained significantly more weight at the end of the study (Table 1), but the weight changes in the ALN treated animal were comparable with and not significantly different from the OVX animals with vehicle treatment.

Discussion

Under healthy conditions, articular cartilage and the underlying subchondral bone act together to transmit pressure, tension, and shear through joint movement. Subchondral bone sclerosis has been considered as a typical feature for OA. It has been hypothesized that increased subchondral bone stiffness leads to reduction in the ability to dissipate the load and distribute the strain and thus initiates or accelerates the cartilage degeneration [22], [30]. Early subchondral bone loss was detected

Conclusions

Our results demonstrated that OVX in older rats induced both OP and OA. Early treatment of OP with ALN protected both articular cartilage and subchondral bone. Late ALN treatment starting at 8 weeks after OVX was able to inhibit subchondral bone loss and slow down the progression to OA but did not reverse cartilage erosion. These results indicate that the subchondral bone plays an important role in OA pathogenesis, particularly in cases of combined OP and OA. Moreover, our results suggest that

Acknowledgments

This study is supported by grants (No. 81070850; No. 81278810; No. 81028005) from the Committee of National Natural Science Foundation, the Program for Excellent Young Scholar in Sichuan University, and the Program for New Century Excellent Talents in University of China.

References (41)

  • C. Sanchez et al.

    Mechanical loading highly increases IL-6 production and decreases OPG expression by osteoblasts

    Osteoarthritis Cartilage

    (2009)
  • A.M. Taylor et al.

    The role of calcified cartilage and subchondral bone in the initiation and progression of ochronotic arthropathy in alkaptonuria

    Arthritis Rheum

    (2011)
  • Y.H. Sniekers et al.

    Oestrogen is important for maintenance of cartilage and subchondral bone in a murine model of knee osteoarthritis

    Arthritis Res Ther

    (2010)
  • K.D. Ham et al.

    Effects of long-term estrogen replacement therapy on osteoarthritis severity in cynomolgus monkeys

    Arthritis Rheum

    (2002)
  • J.A. Roman-Blas et al.

    Osteoarthritis associated with estrogen deficiency

    Arthritis Res Ther

    (2009)
  • J.E. Brouwers et al.

    Bone degeneration and recovery after early and late bisphosphonate treatment of ovariectomized wistar rats assessed by in vivo micro-computed tomography

    Calcif Tissue Int

    (2008)
  • E. Perilli et al.

    Detecting early bone changes using in vivo micro-CT in ovariectomized, zoledronic acid-treated, and sham-operated rats

    Osteoporos Int

    (2010)
  • M. Bellido et al.

    Subchondral bone microstructural damage by increased remodelling aggravates experimental osteoarthritis preceded by osteoporosis

    Arthritis Res Ther

    (2010)
  • S.C. Mastbergen et al.

    Changes in subchondral bone early in the development of osteoarthritis

    Arthritis Rheum

    (2011)
  • D. Doré et al.

    Subchondral bone and cartilage damage: a prospective study in older adults

    Arthritis Rheum

    (2010)
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    All authors have no financial or personal relationship with other people or organizations that could potentially and inappropriately influence their work and conclusions.

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