Bone resorption inhibitor

BACKGROUND: Benefits and risks of a combined hormone replacement therapy (HRT) based on randomized clinical trial emerged on various disease endpoints in 2002. The Women's Health Initiative (WHI) provides an important health answer for healthy postmenopausal women, such as do not use combined HRT to prevent chronic disease, because of the elevated risk of coronary artery disease (CHD), stroke and venous thromboembolism. In March 2004, the NIH stopped the drugs in the estrogen-alone trial after finding an increase risk of stroke and no effect, neither an increase or a decrease, on risk of CHD after an average of 7 years in the trial. On the other hand, raloxifene, which does not seem to significantly increase the risk of cardiovascular events and could retain skeletal benefits without stimulating endometrial and breast tissue, requires decision-makers since no current data on these disease clinical endpoints have been published. OBJECTIVE: To construct a multi-disease model based on patient-specific risk factor profiles, and to validate the multi-disease model with several tools of internal and external validities. METHODS: A Markov state model was developed. The risks of these various diseases (including coronary artery disease, stroke, hip fracture and breast cancer) are derived from published hazards proportional models which take into account significant risk factors. Canadian-specific rates and data sources for these transition probabilities are derived from published studies and Canadian Health Statistics. The validation of our model were based on several tools of internal and external validities, such as Canadian life expectancy, population-based incidence rate of diseases, clinical trials and other published life expectancy models. RESULTS: First, presumably, small changes in the lifetime probability of dying support the hypothesis that the disease states operate in a largely independent fashion. For instance, the difference in the probability of dying from a particular disease by the complete elimination of a selected disease, such as CHD, stroke or breast cancer, ranged from 0.2 to 2.2% of difference in the lifetime probability of dying of these diseases. Second, we demonstrated that the model adequately predicted the Canadian population lifetable and disease-incidence rates from population-based data among women from 45 to 75 years old. The predictions of the model were cross-checked from non-source data, such as predicted outcomes versus observed outcomes from results of clinical trials. Predicted relative risks of CHD event, breast cancer and hip fracture fell in the reported 95% confidence interval of clinical trials. Finally, predicted treatment benefits are comparable with those of published life expectancy models. CONCLUSIONS: The results of the study demonstrated that this multi-disease model, including coronary artery disease, stroke, hip fracture and breast cancer, is a valid model to predict the impact on life expectancy or number of events prevented for preventive pharmacological interventions.

Although neither calcium nor vitamin D has been shown to prevent osteoporosis in postmenopausal women alone, the combination does. Both calcium and vitamin D are commonly used in the treatment of osteoporosis. The estrogens and raloxifene both prevent bone loss in postmenopausal women, and the estrogens probably also decrease the risk of first fracture. There is good evidence that raloxifene prevents further fractures in postmenopausal women who have already had fractures and some evidence that estrogen does as well. Calcitonin increases bone mineral density in early postmenopausal women and men with idiopathic osteoporosis, and also reduces the risk of new fractures in osteoporotic women. The bisphosphonate alendronate prevents bone loss and reduces fractures in healthy and osteoporotic postmenopausal women, and in osteoporotic men. Risedronate is more potent and has fewer upper gastrointestinal side effects than alendronate, and reduces the incidence of fractures in osteoporotic women. Intermittent use of the potent bisphosphonate zoledronate also increases bone mineral density and may become an alternative in the prevention and treatment of osteoporosis. All of the agents discussed above prevent bone resorption, whereas teriparatide increases bone formation and is effective in the treatment of osteoporotic women and men. In the treatment of secondary osteoporosis associated with the use of glucocorticoids to treat inflammation or prevent rejection after transplantation, the bisphosphonates are effective. The agents that have undergone some clinical trialing as new or alternative drugs for the treatment of osteoporosis include tibolone, new SERMs, androgens, growth hormone, insulin-like growth factor-1 and stontium ranelate. The targets/drugs that are being developed to inhibit bone resorption include the OPG/ RANKL/RANK system, cathepsin K inhibitors, vitronectin receptor antagonists, estren, the interleukin-6 and gp130 system, cytokines and growth factors. New drugs/targets to promote bone formation include the commonly used lipid-lowering statins and the calcilytic release of PTH.

Regulation of bone remodeling and emerging breakthrough drugs for osteoporosis and osteolytic bone metastases. Major advances have been made in the past 10 years in our understanding of the molecular basis of bone cell formation and bone remodeling. For example, the discovery of osteoprotegerin, the decoy receptor and inhibitor of receptor activator of NF-kappaB ligand (RANKL), and the RANKL/receptor activator of NF-kappaB (RANK) signaling pathway that is essential for osteoclastogenesis, has helped clarify the mechanisms regulating osteoclast formation, activation, and survival. PTH, like most other osteoclast stimulating factors, promotes RANKL production by osteoblast/stromal cells when they are exposed to it continuously, but when given intermittently it stimulates bone formation and reduces fracture risk in postmenopausal women. This anabolic effect is associated with increased expression of insulin-like and fibroblast growth factors and decreased osteoblast apoptosis. Src tyrosine kinase is essential for osteoclast activation and also negatively regulates osteoblast activity. Thus, it is a well-validated therapeutic target for the prevention of postmenopausal and other forms of bone loss. Preliminary in vitro and in vivo studies of specifically designed, bone targeted, non-peptide Src inhibitors have shown that these compounds inhibit bone resorption and stimulate new bone formation. The design of drugs using structure/function approaches such as this should lead to the development of novel therapeutics that could be used to counteract the negative effects of chronic renal failure on the skeleton.

Statins are widely used lipid-lowering drugs that reduce cholesterol synthesis by inhibiting 3-hydroxy-3-glutaryl-coenzyme A (HMG-CoA) reductase activity. They also strongly stimulate bone formation in rodents. If the drugs' potent bone-building activity results directly from inhibition of HMG-CoA reductase, there should be less bone fracturing in humans who have taken statins to lower their serum cholesterol and prevent heart attacks, but the data gleaned from several databases are contradictory. According to some reports the lipid-lowering doses of oral statins increased bone mineral density and more than halved the risk of fracturing various bones, while according to others, including the very large Women's Health Initiative Observational Study (WHI-OS), the drugs did not significantly affect the fracturing risk. Such contradictory data could be due in part to one of the commonly used statins, pravastatin which only targets hepatocytes, or due to bone growth being stimulated by something other than inhibition of HMG-CoA reductase. Therefore, different doses of statins may be needed to build bone or optimally lower serum cholesterol. To be able to answer the question posed by the title of this editorial, it will be necessary to carry out a controlled trial using designer statins that are less liver-oriented and thus better for assessing the optimal doses needed, specifically for osteogenicity rather than for their cholesterol-lowering ability.

Eli Lilly says Forteo increases spine mineral density fivefold vs Fosamax

Eli Lilly & Co said patients treated with its osteoporosis drug teriparatide showed a five-times greater bone mineral density in the spine compared to patients treated with Merck & Co's alendronate (Fosamax).

The results of the six-month study were presented at the World Health Organization's international symposium on osteoporosis and osteoarthritis in November.

Teriparatide is currently under review by the European Medical Evaluation Agency and the US Food and Drug Administration. It will be marketed under the name Forteo except for in the EU, where it will be called Forsteo. Merck's alendronate is sold under the name Fosamax.

"This is the first time these two drugs have been compared using the potential marketed dose of teriparatide and the marketed dose of alendronate," the Lilly statement quoted Michael McClung MD, of the Oregon Osteoporosis Center, Portland, OR, as saying.