Alendronate protects against articular cartilage erosion by inhibiting subchondral bone loss in ovariectomized rats
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 drugs therapy of combined OP and OA.
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ABSTRACT: Bisphosphonates are considered potential disease modifying osteoarthritis (OA) agents. The present study investigated the efficacy of pre-emptive, early, and delayed alendronate (ALN) treatment initiation on subchondral trabecular bone and cartilage in low-dose monosodium iodoacetate (MIA)-induced knee osteoarthritis (OA) in rats. Male rats received pre-emptive (n=12, day 0 - end of week 2), early (n=12, end of week 2 - end of week 6), or delayed (n=12, end of week 6 - end of week 10) ALN treatment (30 μg/kg/week). Pre-emptive ALN-treated rats were micro-CT scanned in vivo after 2 weeks and then sacrificed, early ALN-treated rats were scanned after 2 and 6 weeks and sacrificed, and the delayed ALN-treated rats were scanned after 2, 6, and 10 weeks of OA induction and sacrificed. After sacrifice, bone histomorphometry and histology of the tibia and biomarker analyses were undertaken. Changes in hind limb weight bearing were assessed from day -1 until day 14. MIA induced pathological features similar to progressive human OA in the cartilage and subchondral bone. Pre-emptive ALN treatment preserved subchondral trabecular bone microarchitecture, prevented bone loss, decreased bone turnover and joint discomfort. Pre-emptive ALN treatment had moderate effects on cartilage degradation. Early and delayed ALN treatments prevented loss of trabeculae and decreased bone turnover, but had no significant effect on cartilage degradation. ALN prevented increased bone turnover and preserved the structural integrity of subchondral bone in experimental OA. The time point of treatment initiation is crucial for treating OA. Treating both the subchondral bone and cartilage in OA would be clinically more beneficial.Osteoarthritis and Cartilage 07/2013; 41(10). DOI:10.1016/j.joca.2013.06.020 · 4.66 Impact Factor
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ABSTRACT: Octacalcium phosphate (OCP) interaction with alendronate (AL) solution results in the complete digestion of OCP: calcium ion is recruited by the bisphosphonate to yield quantitative precipitation of crystalline calcium alendronate monohydrate. This compound improves osteoblast differentiation and inhibits osteoclast proliferation and activity, both alone and, even more, in combination with OCP.Advanced Materials 09/2013; 25(33). DOI:10.1002/adma.201301129 · 15.41 Impact Factor
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ABSTRACT: Osteoarthritis (OA) joints display relevant microstructure alterations associated to an increase in remodeling at subchondral bone, which supports its crucial role in OA pathogenesis. Despite this, the treatment of knee OA patients with antiresorptive drugs has given discordant results, suggesting the existence of a particular patient subset with good response to halting high subchondral remodeling. To identify an OA phenotype that may obtain major benefit from therapy with bone-acting agents. A systematic review of the literature was performed by searching the Medline and PubMed databases from 1990 to April 2013 using the following keywords: subchondral bone, articular cartilage, and osteoarthritis in various combinations with bone agents, bone mineral density, and scintigraphy. Early animal and human studies provided the rationale for the beneficial use of bone agents on OA cartilage damage. Several bone-acting agents have reduced low back pain and likely spondylosis progression. Recently, strontium ranelate has been reported to exert both structural and clinical benefits in knee OA patients with radiological progression. However, other antiresorptives have shown divergent results. Human studies suggest that these contradictory results may be due to the lack of well-defined OA phenotypes and an accurate methodology to recruit and follow up these patients. A particular subset of postmenopausal patients with high remodeling and/or low subchondral bone density may benefit from the treatment with bone-acting agents hindering OA progression. This OA population could be identified with the simultaneous use of subchondral bone dual-energy X-ray absorptiometry and scintigraphy.Seminars in arthritis and rheumatism 09/2013; 43(4). DOI:10.1016/j.semarthrit.2013.07.012 · 3.63 Impact Factor