Bone disease drugs

Fleisch H. Bisphosphonates—pharmacology and use in the treatment of tumor-induced hypercalcemic and metastatic bone-disease. Drugs 1991 42 919-944. 

Vemejoul, M-C de. 1998. Markers of bone remodelling in metabolic bone disease. Drugs Aging l(Suppl. 1), 9-14. 

Bobba RS, Beattie K, Parkinson B, Kumbhare D, Adachi JD. Tolerability of different dosing regimens of bisphosphonates for the treatment of osteoporosis and malignant bone disease. Drug Saf 2006 29 1133-1152. 

Dunn, C.J. et al. (1994) Etidronic acid. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs Aging, 5.446-474. Patel. S. (1996) Current and potential future drug treatments for osteoporosis. Ann. Rheum. Dis.. 55. 700-714. 

Rosen, C.J. et al (1996) Comparative clinical pharmacology and therapeutic use of bisphosphonates in metabolic bone diseases. Drugs, 51. 537-551. 

Due to its anti-resorptive effects, calcitonin has been widely used to treat a variety of metabolic bone diseases, including osteoporosis. However, the availability of more potent drugs has lead to a decline in the clinical use of calcitonin. 

Furthermore, peptidomimetic SH2 domain inhibitors for Src, such as AP-22408 have been designed that interfere with effector binding and thereby disrupt signal transduction. AP-22408 decreases bone resorption in animal studies and may be a promising drug to treat osteoporosis and other bone diseases, such as Paget s disease and osteolytic bone metastasis. 

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. 

Bisphosphonates are drugs of great interest in a number of metabolic bone diseases [119]. This therapeutic class comprises bis(phosphonic acids) and, more recently, bis(phosphonic acid) esters. The former are hydrophilic and poorly bioavailable, and they are generally not metabolized. In contrast, bis(phosphonic acid) esters may be more prone to biotransformation, as exemplified with the lead compound known as U-91502 (9.51 in Fig. 9.11). 

W. K. Sietsema, F. H. Ebetino, Bisphosphonates in Development for Metabolic Bone Disease , Exp. Opin. Invest. Drugs 1994, 3, 1255-1276. 

In mild forms of malabsorption, vitamin D (25,000-50,000 units three times per week) should suffice to raise serum levels of 25(OH)D into the normal range. Many patients with severe disease do not respond to vitamin D. Clinical experience with the other metabolites is limited, but both calcitriol and calcifediol have been used successfully in doses similar to those recommended for treatment of renal osteodystrophy. Theoretically, calcifediol should be the drug of choice under these conditions, because no impairment of the renal metabolism of 25(OH)D to l,25(OH)2D and 24,25(OH)2D exists in these patients. Both calcitriol and 24,25(OH)2D may be of importance in reversing the bone disease. However, calcifediol is no longer available. 

However, potential therapeutic interventions require randomized prospective studies. Variables that might be addressed in such trials include the impact of monotherapy and polytherapy on the attainment of peak bone mass in adolescence and adulthood bone health in women characterization of the impact of limitations in physical activity on bone density in patients with epilepsy who have cerebral palsy or those with developmental disabilities or mental retardation the effects of newer antiepileptic drugs on bone metabolism standardization of the workup for bone disease in patients with epilepsy and the effectiveness of the current recommendations for supplementation with calcium and vitamin D. 

After persistent hypercalciuria, osteopenia can develop, causing metabolic bone disease, pathological fractures, and immobilization. Hypercalciuria can also lead to nephrolithiasis and nephrocalcinosis, factors that can impair renal function. Intravenous chlorothiazide has been successfully used for its hypocalciuric effect, with remarkable effect over a period of 6 months in a 13-year-old child who had received parenteral nutrition for 6 years. Calcium excretion and tubular reabsorption of phosphate returned to normal (48). What is not clear from this study is whether the drug actually has a positive long-term beneficial effect on metabolic bone disease. 

Metabolic bone disease in children receiving parenteral nutrition manifests primarily as osteopenia and, on occasion, fractures (5). The etiology is multifactorial calcium and phosphate deficiency play a major role in the preterm infant but the part played by aluminium toxicity in this population is unknown. Lack of reference values of bone histomorphometry in the premature infant, as well as lack of reference data for biochemical markers of bone turnover in these patients, contributes to the uncertainty. Other factors that may play a role in the pathogenesis of bone disease associated with parenteral nutrition include lack of periodic enteral feeding underljdng intestinal disease, including malabsorption and inflammation the presence of neoplasms and drug-induced alterations in calcium and bone metabohsm. However, the true incidence and prevalence of parenteral nutrition-associated bone abnormalities in pediatric patients are unknown. 

Aluminum-related bone disease can be diagnosed and treated with deferoxamine, an avid chelator of both iron and Al. The deferoxamine infusion test is useful for the ultimate diagnosis of Al overload disease, and the drug has demonstrated utility for treating acute Al overload. ... 

In many analytical applications in biomedical and pharmaceutical sciences it is desirable to probe, noninvasively, the composition of deep layers of samples with high chemical specificity. Examples include the diagnosis of bone disease and breast cancer, as well as the noninvasive probing of pharmaceutical products in quality control applications and drug authentication. 

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