Osteoporosis Major Causes and Therapies

Just as inflammation enhances bone resorption by increasing ODF production locally, the cessation of estrogen production at menopause causes osteoporosis systemically (ODF production increases). Menopausal women therefore suffer a net loss of bone because ODAR (RANK) is activated by ODF (RANKL) in the absence of a compensating increase in OCIF (OPG) production. The osteoclasts demineralize bone faster than the osteoblasts deposit it. 

Mice overexpressing acid phosphatase (Acp5) develop osteoporosis whereas mice lacking this enzyme have decreased bone resorption and develop mild osteopetrosis (overly dense, brittle bones). Fluoride at 0.12 mM (2.3 ppm) inhibits Acp5b and stimulates osteoblast bone deposition in vitro, but fluoride therapy does not inhibit human osteoporosis (Sect. 16.2.2). 

Because bisphosphonates remain tightly bound to the bone surface and cannot be hydrolyzed, they also retard demineralization. Modifications of the side chains attached to the central carbon atom (Fig. 10.6) has yielded compounds such as alendronate (Fosamax), 

Cathepsin K inhibitors would prevent bone loss without inhibiting mineralization. The compound most tested, Balicatib, forms a covalent bond with the cysteine thiol group at the catalytic center of cathepsin K. Unfortunately, Balicatib tends to concentrate in all lysosomes, so that, over time, amounts in the body will increase and inhibit the catalytic thiol group of other cathepsins, notably cathepsin S which hydrolyzes proteins to peptides for antibody synthesis (antigen presentation). Nevertheless, no adverse side effects were reported in 140 postmenopausal women receiving once-a-day treatment with Balicatib for 12 months, but the possibility of increased infections after some years of taking Balicatib is a potential therapeutic problem. 

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