Osteoporosis: Hirsh J

Hirsh J, Bauer KA, Donati MB, Gould M, Samama MM, Weitz JI, Anonymous00126. · Henderson Research Centre, Hamilton Civic Hospitals, 711 Concession Street, Hamilton, Ontario, Canada. · Chest. · Pubmed #18574264 links to  free full text

Abstract: This chapter describes the pharmacology of approved parenteral anticoagulants, including the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin factor Xa and other clotting factors. Heparin also binds to cells and other plasma proteins, endowing it with unpredictable pharmacokinetic and pharmacodynamic properties, and can lead to nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and have a lower risk of nonhemorrhagic side effects. LMWHs can be administered once or twice daily by subcutaneous injection, without anticoagulant monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin; therefore, HIT and osteoporosis are unlikely to occur. Fondaparinux has excellent bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without anticoagulant monitoring. Three parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in HIT patients.

Hirsh J. · Hamilton Civic Hospital Research Center and McMaster University, Hamilton, Ontario, Canada. · Semin Hematol. · Pubmed #11449338 No free full text.

Abstract: In recent years, academic research institutions have increasingly sought to commercialize their discoveries, providing the opportunity to raise venture capital and benefit financially from their developments. In the last 6 years, Hamilton Civic Hospitals Research Center, affiliated with McMaster University, Ontario, Canada, has set up two companies, Vascular Therapeutics and Osteokine, to commercialize its discoveries in thrombosis and osteoporosis. Epidemiological evidence shows a continuing socioeconomic burden of both of these disorders, thereby offering opportunities for new drug development. Key areas in the field of thrombosis include novel parenteral anticoagulants to replace heparin as adjunctive therapy in acute coronary syndromes, safer and more practical oral anticoagulants that do not require monitoring to replace coumarins, and oral antiplatelet drugs for use in combination with aspirin. Since their creation, Vascular Therapeutics and Osteokine have attracted major funding and developed several patentable compounds that show clinical and commercial promise.

Shaughnessy SG, Hirsh J, Bhandari M, Muir JM, Young E, Weitz JI. · Departments of Pathology and Medicine, McMaster University and the Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada. · Blood. · Pubmed #9949165 links to  free full text

Abstract: Although it is well established that long-term heparin therapy causes osteoporosis, it is unknown whether heparin-induced bone loss is reversible when heparin treatment is stopped. To address this question, we randomized rats to once daily subcutaneous injections of either unfractionated heparin (1.0 U/g or 0.5 U/g) or saline for 28 days and then followed the rats for an additional 28 days off treatment. Based on histomorphometric analysis of the distal third of the right femur proximal to the epiphyseal growth plate, 1.0 U/g heparin caused a 30% loss in cancellous bone volume over the first 28 days. This was accompanied by a 137% increase in osteoclast surface and a 60% decrease in both osteoblast and osteoid surface. One month after cessation of heparin treatment, no recovery in these parameters was observed. Similarly, serum levels of alkaline phosphatase, a biochemical marker of bone formation, which continued to decrease over the course of heparin treatment, showed no signs of recovery in the subsequent 28 days off treatment. To explore the mechanism responsible for the prolonged effect of heparin on bone, we repeated the experiment giving 125I-labeled heparin in place of unlabeled heparin. 125I-labeled heparin was found to accumulate in bone during the course of its administration, and be retained in bone for at least 56 days after stopping heparin treatment. These findings suggest that heparin-induced osteoporosis is not rapidly reversible because heparin is sequestered in bone for an extended period.