Osteoporosis trials

Human growth hormone, used as a human pharmaceutical, is approved for only one indication in the United States, treatment of growth failure owing to hGH deficiency, a condition known as pituitary dwarfism. However, clinical trials are under way to test its efficacy in Turner s syndrome, bums, wound healing, cachexia, osteoporosis, constitutional growth delay, aging, malnutrition, and obesity. 

PTKs have been implicated in the regulation of a variety of biological responses such as cell proliferation, migration, differentiation, and survival. They have been demonstrated to play significant roles in the development of many disease states, including immunodeficiency, atherosclerosis, psoriasis, osteoporosis, diabetes, and cancer. In recent clinical trials impressive antitumor effects of PTK inhibitors have been observed. In future, PTK inhibitors may therefore become important drugs for the treatment of specific cancers. 

Several other inhibitors of nonreceptor PTKs are currently in development but only a few of them are studied in clinical trials. Noteworthy, Dasatinib does not only inhibit c-Abl, but also potently blocks Src activity, a property that may contribute to its beneficial clinical effects in CML. Other kinase inhibitors being developed that inhibit c-Abl and/or Src are AZD-0530, AP-23994, PD-0183805, SU-6656, and Bosutinib (SKI-606). Furthermore, peptidomimetic SH2 domain inhibitors for Src, such as AP-22408 have been designed that decrease bone resorption and may be promising drugs to treat osteoporosis and other bone diseases, such as Paget s disease and osteolytic bone metastasis. 

Vitamin C status is supposed to play a role in immune function and to influence the progression of some chronic degenerative diseases like atherosclerosis, cancer, cataracts, and osteoporosis. The role of vitamin C in immune function, especially during common cold and upper respiratory tract infection, is the subject of lively debate. The exact mechanisms of action have not yet been fully elucidated, but the results of several trials point to a reduced duration and intensity of infections in subjects consuming high amounts of vitamin C (200-1000 mg/d). However, the incidence of common cold was not influenced significantly (24). 

In order to get recent advances on the effects of phytoestrogens on hormonal-dependent diseases as well as on human supplementation trials, it might be useful to refer to http //www.venus-ca.org/ (EU-funded project on dietary exposure to phytoestrogens and related compounds and effects on skeletal tissues) http //www.phytos.org (EU-funded project on the prevention of osteoporosis by nutritional phytoestrogens) http //www.phytoprevent.org (EU-funded project on the role of phytoestrogens in the prevention of breast and prostate cancer) and http //www.nutrition.tum.de/isoheart.htm (EU-funded project on cardiovascular health of postmenopausal women). 

The growth and spread of thyroid carcinoma is stimulated hy TSH. An important component of thyroid carcinoma management is the use ofLT4 to suppress TSH secretion. Early in therapy, patients receive the lowest LT4 dose sufficient to fully suppress TSH to undetectable levels. Controlled trials show that suppressive LT4 therapy reduces tumor growth and improves survival. These patients are purposefully overtreated with LT4 and rendered subclinically hyperthyroid. Postmenopausal women should receive aggressive osteoporosis therapy to prevent LT4-induced bone loss. Other thyrotoxic complications, such as atrial fibrillation, should be monitored and managed appropriately. 

HOPE Women s Health, Osteoporosis, Progestin/Estrogen trial... 

Thiazide diuretics decrease urinary calcium excretion and may decrease bone turnover. However, their effects on bone mineral density and fracture rates have not been studied in controlled trials. Thiazide diuretics are not recommended solely for potential beneficial effects in osteoporosis. 

Interest in the role of HMG-CoA reductase inhibitors (statins) in the treatment of osteoporosis came from boneforming properties seen in animal studies. However, controlled clinical trials are needed. 

Compared with postmenopausal osteoporosis, few clinical trials have been conducted evaluating therapies in men. Although alendronate and calcitonin have both been studied, only alendronate reduces fracture rates in men. Teriparatide also has been studied, but no data are available yet on fracture rates. At this time, alendronate and teriparatide are approved by the FDA for the treatment of osteoporosis in men. Owing to proven benefit in reducing fractures and relative safety, alendronate should be considered first-line treatment for primary osteoporosis in men. Teriparatide should be reserved as alternate therapy in this population. 

In leukemia, the intensified use of methotrexate and glucocorticoids is responsible for causing an increased frequency of neurotoxicity and, in older children and adults, avascular necrosis of bone. High cumulative doses of anthracyclines can cause cardiomyopathy. Cranial irradiation causes neuropsychologic deficits and endocrine abnormalities that lead to obesity, short stature, precocious puberty, and osteoporosis.3 As newer and more intensive treatments enter clinical trials, close observation for long-term side effects will assume even greater importance.24... 

Miproxifene (TAT-59) is a prodrug of 4-hydroxy-tamoxifen that has been developed for tamoxifen-resistant carcinoma, but relatively little information has been published on this drug. Compared with tamoxifen, miproxifene inhibits estradiol-stimulated proliferation of MCF-7 cells at a threefold lower dose than that of tamoxifen, and of dimethyl-benzanthracene (DMBA)-induced rat mammary tumors at a dose tenfold lower than tamoxifen (Toko et al. 1990). In any event, in preclinical castrated rat models, it shows an endometrial stimulation activity that is similar to that of tamoxifen, which means it has limited potential use in the prevention or treatment of osteoporosis or cardiovascular disease (Shibata et al. 2000). Similarly, considering the preclinical findings of endometrial stimulation reported on GW5638 (Willson et al. 1997), it is likely that this new SERM belonging to the triphenylethylene family will be limited in clinical use to the treatment of advanced tamoxifen-resistant breast cancer once its efficacy is demonstrated in human clinical trials. 

Clinical trials on postmenopausal women with osteoporosis have demonstrated that raloxifene reduces bone turnover markers by 25-35% after 1 year of treatment and reduces the relative risk of the occurrence of new vertebral fractures by 30-50% after 3 years of treatment (Ettinger et al. 1999). A post hoc analysis in women at high risk for cardiovascular diseases also showed a reduction of 40% in the rate of new cardiovascular events (Barrett-Connor et al. 2002), with no observed reduction in the overall study population after 4 years of treatment in the MORE trial. 

Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. Results from a 3-year randomized clinical trial. J Am Med Assoc 282 637-645. Corrections published in J Am Med Assoc 282 2124... 

Chesnut III CH, Silverman S, Andriano K, Genant H, Gimona A, Harris S, Kiel D (2000) A randomised trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis the prevent recurrence of osteoporotic fractures study. Am J Med 109 267-276... 

Delmas PD, Ensrud KE, Adachi JD, Harper KD, Sarkar S, Gennari C, Reginster JY, Pols HAP, Recker RR, Harris ST, Wu W, Genant HK, Black DM, Eastell R for the Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators (2002) Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis four-year results from a randomized clinical trial. J Clin Endocrinol Metab 87 3609-3617... 

Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut III CH, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD for the VERT Study Group (1999) Effects of risedronate treatment on vertebral and non vertebral fractures in women with postmenopausal osteoporosis a randomised controlled trial. J Am Med Assoc 282 1344-1352... 

Kanis JA, Johnell O, Black DM, Downs RW Jr, Sarkar S, Fuerst T, et al. (2003) Effect of raloxifene on the risk of new vertebral fracture in postmenopausal women with osteopenia or osteoporosis a reanalysis of the Multiple Outcomes of Raloxifene Evaluation trial. Bone 33 293-300... 

Liu J, Zhu H, Huang Q, Zhang Z, Li H, Qin Y, Zhang Y, Wei D, Lu J, Liu H, Xen X, Liu Y, Ekangaki A, Zheng Y, Diez-Perez A, Harper K (2004) Effects of raloxifene hydrochloride on bone mineral density, bone metabolism and serum lipids in Chinese postmenopausal women with osteoporosis a multi-center, randomized, placebo-controlled clinical trial. Chin Med J 117 1029-1035 (in English)... 

Lufkin EG, Whitaker MD, Nickelsen T, et al. (1998) Treatment of stablished postmenopausal osteoporosis with Raloxifene a randomized trial. J Bone Miner Res 13 1747-1754... 

Reginster J-Y, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, Lund B for the VERT Study Group (2000) Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int 11 83-91... 

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