Osteoporosis: A Review of Treatment Options.

Approximately 10 million men and women in the U.S. have osteoporosis,1 a metabolic bone disease characterized by low bone density and deterioration of bone architecture that increase the risk of fractures.2 Osteoporosis-related fractures can increase pain, disability, nursing home placement, total health care costs, and mortality.3 The diagnosis of osteoporosis is primarily determined by measuring bone mineral density (BMD) using noninvasive dual-energy x-ray absorptiometry. Osteoporosis medications include bisphosphonates, receptor activator of nuclear factor kappa-B ligand inhibitors, estrogen agonists/antagonists, parathyroid hormone analogues, and calcitonin.3-6 Emerging therapies utilizing novel mechanisms include a cathepsin K inhibitor and a monoclonal antibody against sclerostin.7,8 While professional organizations have compiled recommendations for the management of osteoporosis in various populations, a consensus has yet to develop as to which is the gold standard; therefore, economic evaluations have been increasingly important to help guide decision-makers. A review of cost-effectiveness literature on the efficacy of oral bisphosphonates has shown alendronate and risedronate to be most cost-effective in women with low BMD without previous fractures.9 Guidelines are inconsistent as to the place in therapy of denosumab (Prolia, Amgen). In economic analyses evaluating treatment of postmenopausal women, denosumab outperformed risedronate and ibandronate; its efficacy was comparable to generic alendronate, but it cost more.10 With regard to older men with osteoporosis, denosumab was also found to be cost-effective when compared with bisphosphonates and teriparatide (Forteo, Lilly).11.

Pharmacological Treatment of Insomnia.

Up to 70 million U.S. adults have chronic sleep and wakefulness disorders. Therapies may include prescription medications approved by the Food and Drug Administration, off-label treatments, over-the-counter drugs, and herbal therapies.

The effects of lovastatin on proteasome activities in highly purified rabbit 20 S proteasome preparations and mouse MC3T3-E1 osteoblastic cells.

A number of clinical studies suggest that the use of the lipid-lowering agents collectively referred to as statins (hydroxymethyl glutaryl coenzyme A [HMG-CoA] reductase inhibitors) is associated with increased bone density, reduced fracture risk, and net bone anabolism. Statins (< or =5 micromol/L) stimulate rodent bone formation, but the mechanistic basis remains unclear. Since statins and the proteasome inhibitor lactacystin are structurally similar, and high doses (> or =40 micromol/L) of statins can inhibit the chymotryptic activity of the proteasome, it has been hypothesized that statins exert their anabolic effects on bone, in part, by inhibiting the proteasome, the major eukaryotic intracellular regulatory protease. This hypothesis conflicts with reports that statins stimulate proteasome activity and that proteasome-catalyzed degradation of specific substrates is required for cell proliferation, differentiation, and survival. Our chief objective was to determine the effects of statins (< or =10 micromol/L) on the chymotryptic activity of the proteasome in the 20 S proteasome and intact murine MC3T3-E1 cells cultured to low density (preosteoblasts) or high density (differentiated osteoblasts). Lovastatin (0.001 micromol/L to 5.0 micromol/L) stimulated the chymotryptic activity of the highly purified 20 S proteasome. Preosteoblasts and differentiated osteoblasts treated with 1, 5, or 10 micromol/L lovastatin for 1 hour exhibited morphologic abnormalities that were ameliorated by preincubation and treatment with 20 micromol/L mevalonate. The chymotryptic activity of the preosteoblast proteasome increased after 2 days of 1.0 micromol/L or 5.0 micromol/L lovastatin treatment. In addition, the DNA and protein contents of 1.0 micromol/L or 5.0 micromol/L lovastatin-treated preosteoblast cultures were lower those that observed in vehicle-, 0.01 micromol/L lovastatin-, or 0.10 micromol/L lovastatin-treated cultures. The chymotryptic activity of the proteasome was much lower in differentiated osteoblasts than in preosteoblasts. Two days of treatment with 1 micromol/L lovastatin modestly stimulated the chymotryptic activity of the proteasome in differentiated osteoblasts, but had no effects on total protein or DNA, compared to cultures treated with vehicle or lower doses of lovastatin. Thus, the data support the hypothesis that statins stimulate proteasome activities in highly purified proteasome preparations and preosteoblastic cells. Treating preosteoblastic or differentiated MC3T3-E1 cells with lovastatin concentrations > or = 1 micromol/L resulted in abnormal morphology and reduced the DNA and protein levels in preosteoblastic cultures, confirming the adverse effects of statins previously reported for other cells. In conclusion, the hypothesis that lovastatin exerts its anabolic effects on bone by inhibiting the proteasome activity of the osteoblast was refuted, and the effects of lovastatin on MC3T3-E1 cells were found to be highly dose- and development-dependent.