alendronate, Fosamax
[Bisphosphonates stimulate the production of basic fibroblast growth factor and the formation of bone marrow precursors of osteoblasts. New findings about their mechanism of action]

[Article in Italian]

Giuliani N, Pedrazzoni M, Passeri G, Negri G, Impicciatore M, Girasole G.

Istituto di Clinica Medica Generale e Terapia Medica, Universita degli Studi, Parma.

BACKGROUND: It has been recently shown that bisphosphonates may affect bone resorption either directly on osteoclast activity or through the mediation of osteoblasts activity. In this experimental study the potential effects of etidronate and alendronate on osteoblastic bone formation are investigated. METHODS: The number of fibroblastic colony forming units (CFU-F) and mineralized nodules (CFU-OB) in murine and human bone marrow cultures, assessed. In addition, the basic-FGF production by human osteoblastic cells MG-63 measured. RESULTS: In murine bone marrow cultures etidronate and alendronate stimulate CFU-F formation with a mean increases vs control of 106 +/- 17% at 10(-5) M and 78 +/- 5% at 10(-7) M respectively (p < 0.001). The formation of bone nodules is inhibited by bisphosphonates at high concentrations (> 10(-6) M) and stimulated at lower concentrations (from 10(-7) M to 10(-9) M for etidronate and from 10(-7) M to 10(-10) M for alendronate; p < 0.001). Similarly, in human bone marrow cultures alendronate increases CFU-F formation with a maximal effect at 10(-10) M (+161 +/- 12% vs control; p < 0.01) and the formation of CFU-OB with a maximal effect at 10(-10) M (+133 +/- 34%; p < 0.001). Finally, etidronate (from 10(-9) to 10(-11) M) and alendronate (from 10(-9) to 10(-12) M) stimulate the b-FGF production by human osteoblastic cells (p < 0.01). CONCLUSIONS: In line with previous histomorphometric and clinical observations, the results obtained indicate that bisphosphonates directly affect osteoblastic cells with a positive effect on bone formation, probably via the stimulation of growth factors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9824986&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Alendronate inhibits osteopontin expression enhanced by parathyroid hormone-related peptide (PTHrP) in the rat kidney.

Yasui T, Fujita K, Sasaki S, Iguchi M, Hirota S, Nomura S, Azuma Y, Ohta T, Kohri K.

Department of Urology, Nagoya City University Medical School, Nagoya, Japan.

It has been reported that osteopontin (OPN) plays an important role during urolithiasis as well as bone formation. Generation of stones in the urinary tract may be associated with osteoporosis and bisphosphonates are potent inhibitors of bone resorption, being used with effect in the management of bone disease. We therefore investigated the relationship between alendronate, a bisphosphonate derivative, and OPN expression in the kidney. Alendronate was administered to rats made hypercalcemic by treatment with parathyroid hormone-related peptide (PTHrP). The renal expression of OPN was then evaluated at both protein and mRNA levels. OPN expression was enhanced in the distal tubular cells of hypercalcemic rats and was decreased by alendronate. The observed inhibition of OPN expression suggests an ability of alendronate and other bisphosphonates to act as inhibitors of stone formation in the urinary tract.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9840346&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
[Ulcerative esophagitis associated with the use of alendronate sodium: histopathological and endoscopic features]

[Article in Portuguese]

Fernandes PA, Pires MS, Gouvea AP.

Laborat rio N cleo - Anatomia Patol gica e Citopatologia, Belo Horizonte, MG.

BACKGROUND: Drug-induced or "pill-induced" esophagitis may be secondary to the prolonged contact of the drug with the esophageal mucosa or secondary to the drug ability to alter the local conditions. The alendronate sodium, a bone resorption inhibitor used in the treatment and prevention of osteoporosis, has been cited, recently, as one of the causes of adverse upper gastrointestinal tract injury. AIM: To describe the clinical, endoscopic and histopathological features of patients with ulcerative esophagitis associated with alendronate sodium. PATIENTS: Four women and one man with osteoporosis were treated with alendronate sodium and submitted to endoscopy followed esophageal biopsy. RESULTS: The age range of the patients was from 64 to 84 years old. The patients showed dyspeptic symptoms after taking alendronate sodium during a period of 2-12 months. At endoscopic evaluation, the mucosa was friable, with erosion and/or ulceration covered by fibrin in the distal esophagus. The pathological examination of the esophageal biopsies revealed ulcerative esophagitis characterized by necrofibrinpurulent material, granulation tissue, and yellow refractile polarizable crystal. The patients' symptoms resolved after stopping alendronate sodium use. CONCLUSIONS: The esophagus injuries associated with alendronate sodium are not frequent and seem to be associated with the incorrect use of medication. The endoscopists and pathologists should be alert to the possibility of alendronate sodium therapy in cases of diagnosis of ulcerative esophagitis in ancient patients, particularly in women. The recognition of this condition would improve the patient care.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12778309&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro.

Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, Wesolowski G, Russell RG, Rodan GA, Reszka AA.

Department of Bone Biology/Osteoporosis Research, Merck Research Laboratories, West Point, PA 19486, USA.

Nitrogen-containing bisphosphonates were shown to cause macrophage apoptosis by inhibiting enzymes in the biosynthetic pathway leading from mevalonate to cholesterol. This study suggests that, in osteoclasts, geranylgeranyl diphosphate, the substrate for prenylation of most GTP binding proteins, is likely to be the crucial intermediate affected by these bisphosphonates. We report that murine osteoclast formation in culture is inhibited by both lovastatin, an inhibitor of hydroxymethylglutaryl CoA reductase, and alendronate. Lovastatin effects are blocked fully by mevalonate and less effectively by geranylgeraniol whereas alendronate effects are blocked partially by mevalonate and more effectively by geranylgeraniol. Alendronate inhibition of bone resorption in mouse calvaria also is blocked by mevalonate whereas clodronate inhibition is not. Furthermore, rabbit osteoclast formation and activity also are inhibited by lovastatin and alendronate. The lovastatin effects are prevented by mevalonate or geranylgeraniol, and alendronate effects are prevented by geranylgeraniol. Farnesol and squalene are without effect. Signaling studies show that lovastatin and alendronate activate in purified osteoclasts a 34-kDa kinase. Lovastatin-mediated activation is blocked by mevalonate and geranylgeraniol whereas alendronate activation is blocked by geranylgeraniol. Together, these findings support the hypothesis that alendronate, acting directly on osteoclasts, inhibits a rate-limiting step in the cholesterol biosynthesis pathway, essential for osteoclast function. This inhibition is prevented by exogenous geranylgeraniol, probably required for prenylation of GTP binding proteins that control cytoskeletal reorganization, vesicular fusion, and apoptosis, processes involved in osteoclast activation and survival.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9874784&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Treatment of children with Osteogenesis imperfecta in Estonia.

Maasalu K, Haviko T, Martson A.

Department of Traumatology and Orthopaedics, Tartu University Clinics, Tartu, Estonia.

AIM: To analyse the changes in fracture rate, bone density and histology in children with Osteogenesis imperfecta receiving treatment with alendronate (oral bisphosphonate) and calcitriol. METHODS: Children treated at Tartu University Hospital from 1995 to 2001 were examined for Osteogenesis imperfecta. Radiographs and bone density measurements were obtained for all patients at the beginning of the study. Four patients also had bone biopsies prior to and one year after beginning treatment. The children were then given alendronate in weight-dependent dosages and also calcitriol. The number of fractures during the treatment period was recorded and follow-up bone density measurements were made. RESULTS: Fifteen patients were treated during the 6-y period; mean follow-up approximately 3 y. It was found that the number of bone fractures had decreased significantly (p < 0.0001). Bone density improved in all 15 patients. Histologic studies revealed an increased number of osteoblasts and thickness of bone trabeculae as well as a more regular bone lamellar structure at the time of the second operation. CONCLUSION: The complex treatment of Osteogenesis imperfecta should include alendronate and calcitriol to decrease fractures and improve bone mineral density.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12801112&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Transient osteoporosis of the navicular bone in a runner.

Miltner O, Niedhart C, Piroth W, Weber M, Siebert CH.

Orthopaedic Department of the UK Aachen, Pauwelsstr. 30, 52074, Aachen, Germany.

INTRODUCTION. Transient osteoporosis or the bone marrow oedema syndrome is described as a self-limiting disorder. Transient osteoporosis usually affects only one bone, predominantly the proximal femur. Involvement of the foot is rare and often overlooked. A disorder of the navicular bone of the foot can be found twice in the literature. MATERIALS AND METHODS. We report a case of transient osteoporosis of the navicular bone of the foot in a 20-year-old, female, top-level track athlete (400 m sprinter) treated with alendronate, and a review of the literature. RESULTS. The therapeutic options are limited, frequently consisting of non-specific, symptomatic therapy. Some authors report favourable results with core decompression, while others have reported good results with a conservative regime of symptomatic treatment and avoidance of weight-bearing until the clinical and radiological changes have resolved. In the described case, the patient had a favourable result after a short course of treatment with alendronate. She experienced almost immediate pain reduction and presented a complete resolution of the abnormal signal intensity on MRI. CONCLUSION. This rapid result makes the use of alendronate seem promising in athletes with transient osteoporosis, permitting an early return to high-level activities.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12802601&dopt=Abstract alendronate Fosamax