The coupling of bone and cartilage turnover in osteoarthritis: opportunities for bone antiresorptives and anabolics as potential treatments?

Abstract

Osteoarthritis (OA) is the most common form of arthritic disease, and a major cause of disability and impaired quality of life in the elderly. OA is a complex disease of the entire joint, affecting bone, cartilage and synovium that thereby presents multiple targets for treatment. This manuscript will summarise emerging observations from cell biology, preclinical and preliminary clinical trials that elucidate interactions between the bone and cartilage components in particular. Bone and cartilage health are tightly associated. Ample evidence has been found for bone changes during progression of OA including, but not limited to, increased turnover in the subchondral bone, undermineralisation of the trabecular structure, osteophyte formation, bone marrow lesions and sclerosis of the subchondral plate. Meanwhile, a range of investigations has shown positive effects on cartilage health when bone resorption is suppressed, or deterioration of the cartilage when resorption is increased. Known bone therapies, namely oestrogens, selective oestrogen receptor modifiers (SERMs), bisphosphonates, strontium ranelate, calcitonin and parathyroid hormone, might prove useful for treating two critical tissue components of the OA joint, the bone and the cartilage. An optimal treatment for OA likely targets at least these two tissue components. The patient subgroups for whom these therapies are most appropriate have yet to be fully defined but would likely include, at a minimum, those with high bone turnover.

Recent advances in the understanding of molecular mechanisms of cartilage degeneration, synovitis and subchondral bone changes in osteoarthritis

“…Changes in the subchondral bone can explain clinical symptoms such as osteophyte formation. The importance of subchondral bone remodeling has been emphasized not only in humans but also in animal models of acquired OA (13). Studies suggest that various factors released from the subchondral bone environment are able to regulate cartilage metabolism (6,13) and could therefore become critical therapeutic target to control the disease, improving both clinical symptoms and joint structural erosion.…”

“…The importance of subchondral bone remodeling has been emphasized not only in humans but also in animal models of acquired OA (13). Studies suggest that various factors released from the subchondral bone environment are able to regulate cartilage metabolism (6,13) and could therefore become critical therapeutic target to control the disease, improving both clinical symptoms and joint structural erosion. This review will summarize the current knowledge on the role of subchondral bone remodeling in the development of OA through the induction of an abnormal phenotype in osteoblasts of subchondral bone and the effects of chondrocytes on subchondral bone.…”

Hand osteoarthritis, menopause and menopausal hormone therapy

“…Targetting bone turnover may be one mechanism by which MHT could interfere with OA [49]. There is recent evidence for disease modification of OA by two bone-acting agents -strontium ranelate and bisphosphonates such as zoledronate, supporting the clinical relevance of other bone-acting agents such as MHT or SERMs (reviewed in [49]). In a crosssectional study, women receiving either estrogen or alendronate had less OA-related bony changes on knee MRI than women not taking these drugs [50].…”

“…2 of the better validated human biomarkers of subsequent matrix degradation in OA are COMP and CTXII. MHT and SERMs such as levormeloxifene and raloxifene reduce levels of both of these markers [38,45,[47][48][49].…”

Pharmacological diversity among drugs that inhibit bone resorption

“…Apart from pain management, there have been more disappointments than successes with attempts at pharmacological therapy. The potential use of anti-resorptive drugs in osteoarthritis remains an attractive option [119 ], based on the notion that modulating the excessive subchondral bone remodelling might be beneficial. Several studies have been conducted with bisphosphonates [120], and there are recent positive studies with strontium [121 ].…”