alendronate, Fosamax
Bisphosphonates: a potential role in the prevention of osteoporosis in laying hens.

Wilson S, Solomon SE, Thorp BH.

Roslin Institute, Midlothian.

Osteoporosis in layers is associated with the modelling and remodelling of medullary bone. Cancellous bone volume (CBV) decreases initially during medullary bone modelling and continues to decrease during subsequent remodelling. In an attempt to maintain peak structural bone mass, the bisphosphonate, alendronate, was administered to pullets before medullary bone modelling. At point of lay CBV was significantly greater (P<0.01) in the alendronate group (17.59 per cent) than in controls (13.79 per cent), while medullary bone volume (MBV) was not significantly affected. After 20 weeks, CBV remained significantly higher (P<0.02) in the alendronate group (12.72 per cent) than in controls (9.80 per cent) and MBV was lower in the alendronate group than the control group. CBV was however reduced and MBV increased in both groups compared with values at point of lay. Alendronate therefore appeared to prevent the bone loss associated with medullary bone modelling but not that which occurs during remodelling.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9557803&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
[Role of bones in the physiopathology of idiopathic hypercalciuria: effect of amino-bisphosphonate alendronate]

[Article in Spanish]

Weisinger JR, Alonzo E, Machado C, Carlini R, Martinis R, Paz-Martinez V, Bellorin-Font E.

Servicio de Nefrologia y Transplante Renal, Hospital Universitario de Caracas, Venezuela.

Previous studies from our laboratory demonstrated that bone mineral content is affected in patients with idiopathic hypercalciuria and that there is a correlation between bone mineral loss and in-vitro cytokine production. At the same time we found that short term treatment with alendronate decreased urinary calcium in these subjects. In the present study we have examined the long-term effects of alendronate treatment (10 mg/day for one year) on urinary calcium, urinary hydroxyproline and bone mineral content in 18 idiopathic hypercalciuric and 8 normocalciuric stone formers. Clinical characteristics, as well as gender and age distribution were similar in both groups. Urinary calcium and hydroxyproline, were measured monthly. Calcium excretion decreased significantly at the end of the first month, and remained lower thereafter (277 +/- 28, before vs. 202 +/- 26 mg/g creatinine, after 12 months on alendronate, p < 0.01). Urinary hydroxyproline decreased significantly during the study (125.5 +/- 32.1 vs. 39.66 +/- 17.5 mg/g creatinine, p < 0.05). Serum calcium, glomerular filtration rate, and urinary sodium, did not change during the study. Lumbar spine bone density (trabecular bone) obtained with X ray absorptiometry revealed a significant increase from 1.162 +/- 0.231 to 1.197 +/- 0.248 g/cm2 (p < 0.01). These changes were associated with a significant decrease in IL-1 alpha mRNA transcription by unstimulated and lipopolysaccharide stimulated blood mononuclear cells, as tested by the reverse transcriptase polymerase chain reaction. No changes were observed in bone cortical sites (femoral neck). Normocalciuric subjects showed no significant changes in urinary calcium. In summary, the changes observed in urinary calcium excretion and different bone metabolic parameters, suggest a role of bone in the pathophysiology of idiopathic hypercalciuria.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9567354&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Pharmacovigilance study of alendronate in England.

Biswas PN, Wilton LV, Shakir SA.

Drug Safety Research Unit, Bursledon Hall, Blundell Lane, SO31 1AA, Southampton, UK.

Alendronate sodium is an aminobiphosphonate, an analog of inorganic pyrophosphate, indicated for the treatment of osteoporosis in post-menopausal women. We analyzed events reported in patients prescribed alendronate by general practitioners (GPs) in England. A non-interventional observational cohort study was conducted using the technique of prescription event monitoring (PEM). Exposure data were obtained from dispensed prescriptions issued between October 1995 and January 1997. Outcome data were obtained by sending questionnaires to prescribing GPs. The cohort comprised 11,916 patients. Events most frequently reported as suspected adverse drug reactions and reason for stopping alendronate were recognized gastrointestinal events listed in the Summary of Product Characteristics. These included nausea/vomiting, abdominal pain, dyspepsia, esophagitis and esophageal reflux. Events with the highest incidence density (ID(1) per 1000 patient months treatment) were dyspeptic conditions (32.2), nausea/vomiting (20.8) and abdominal pain (13.8). The term dyspeptic conditions included dyspepsia, esophagitis, esophageal reflux, duodenitis, gastritis and heartburn. Serious suspected adverse reactions possibly related to alendronate were single reports of angioedema, erythema multiforme, hypercalcemia and hypocalcemia. There were 540 deaths in this elderly cohort. This study suggests that alendronate appears to be well tolerated, though there may be risk of developing gastrointestinal side effects including esophagitis and esophageal ulcers.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12730757&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
[Effects on bone mass of oral alendronate, hormone replacement therapy and combined regimes in post-menopausal women: preliminary report on a comparative study]

[Article in Spanish]

Ulla MR, Araujo GL, Giglione F, Fajreldines F, Domingo P, Noriega R, Rivoira MA.

Centro Privado de Endocrinologia y Osteoporosis, Cordoba, Argentina.

The results of a prospective study that compared the short term effects on skeletal bone of oral alendronate, transdermal hormone replacement therapy (HRT) and two combined regimens with both medications are reported. Ninety six posmenopausal women with osteopenia (WHO classification) in lumbar spine or femoral neck measured by DEXA (table 1) were included in 4 therapeutic groups: Group I (n:19): 17 beta-Estradiol 50 micrograms daily transdermally/medroxiprogesterone 2.5 mg orally per day; Group II (n:42): alendronate 10 mg/day orally; Group III (n:15): HRT + alendronate 10 mg/day and Group IV (n:20): HTR + alendronate 5 mg/day. After 12 month treatment, lumbar bone mineral density (BMD) significantly increased to 3.6%; 4.1%; 6.5% y 3.1% in group I to IV, respectively (p < 0.01; figure 1). Differences among groups do not reached statistical significance. The percentage of responders to medication in each group was of 68.8%; 92%; 90% y 83%, respectively. Bone mineral density in femoral neck (FN) increased with all regimens, though mean values did not surpass method variation coefficient. Differences from baseline were statistically significant in group I (p < 0.05). The percentage of responders in this region was 58.8%; 60%; 62.5% y 45.5%, respectively. Biochemical bone markers (table 2), especially urinary pyridinoline and serum osteocalcin, showed a trend in bone metabolism inhibition that was more sustained in group III, as show mainly by the bone markers pyridinolines and osteocalcin. It is concluded that either single therapy with alendronate or estrogen or their combination halted bone loss in most patients leading to bone mass gain mainly in lumbar spine in the short term. However, bone effects with hormone replacement therapy in association with alendronate 10 mg were comparatively major, indicating the potential benefits of this regimen in the long term.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9567355&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
[Tolerability of oral bisphosponates in patients with osteoporosis and other osteopathies]

[Article in Spanish]

Spivacow R, Roldan EJ, Zanetti D, Piccinni E, Zanchetta JR.

Instituto de Investigaciones Metabolicas (IDIM), Buenos Aires, Argentina.

Oral nitrogen containing bisphosphonates (NCB) are effective drugs to inhibit bone metabolism turnover in osteoporosis and other bone diseases. Notwithstanding, some digestive disturbances create concern on the long term acceptance of the oral route. Side effects are mainly caused by low absorption and poor solubility in digestive content. Therefore the compound may precipitate and irritate the mucosas. Furthermore, the administered amount of a particular molecule, its intrinsic potency to irritate digestive walls and the degree of exposition to such sensitive tissue are other facts that combined, may determine the clinical tolerability. Thus, a single factor cannot predict the clinical tolerability. Pamidronate, alendronate and olpadronate are the main NCB under clinical usage. Alendronate is 10 times more potent than pamidronate but possesses a similar slight solubility (2.4 vs 3.0% W/V respectively). It also seems to be more (3 times fold) ulcerogenic in experimental assays. The current available pamidronate formulation protects from esophagus and gastric exposition. Up to now and until randomized clinical trials be performed the selection of the most tolerated aminobisphosphonate in clinical practice will depend on the interplay of many factors (table 1 shows a hypothetical view). Moreover, different patients may react dissimilarly depending on their sensitivity to a particular factor. Olpadronate is free-soluble (24% W/V), almost equipotent with alendronate (figure 1) and seems to lack relevant irritation potential, but clinical data is on its early phases and is still not available. Micronization of the bisphosphonate preparation may be of help to improve tolerability as shown with newer pamidronate oral formulations. The current clinical published data shows more or less the same safety profile for pamidronate (only when enteric coated capsules are used) as alendronate, with more than 90% of patients complying with long term treatments. Anyway the trials are not entirely comparable as said before. Some other pamidronate formulations proved to be intolerable and have not been accepted. Identifying the many factors of oral NCB's digestive tolerability may help with their clinical management. And in those countries where the two compounds are available they may alternatively be used in the sensitive patients. Finally, extra-digestive side effects, not commented in this article, should also be weighted when selecting a bisphosphonate.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9567364&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Effect of alendronate on cultured normal human osteoblasts.

Garcia-Moreno C, Serrano S, Nacher M, Farre M, Diez A, Marinoso ML, Carbonell J, Mellibovsky L, Nogues X, Ballester J, Aubia J.

Instituto Municipal de Investigacion Medica, Barcelona, Spain.

Alendronate is an aminobisphosphonate with a potent anti-reabsorptive action that does not appear to interfere with bone mineralization, and is even able to increase bone mineral density in osteoporotic postmenopausal women through a still not fully understood mechanism. This study was conducted to assess the direct effect of alendronate on diverse aspects of normal human osteoblast physiology. For that purpose, the in vitro effect of a wide range of concentrations [from 10(-1) to 10(-12) mol/L] of alendronate on cell viability, proliferation, collagen synthesis, and the mineral-depositing capacity of normal human osteoblasts was tested. Alendronate effects were examined at 48 and 96 h of culture in the presence or absence of fetal calf serum. In vitro alendronate affected osteoblast viability at concentrations equal to or higher than 10(-4) mol/L. At concentrations equal to or higher than 10(-3) mol/L, no viable cells were observed in cultures. In vitro alendronate at concentrations between 10(-5) and 10(-12) mol/L did not have any effect on the proliferative capacity of normal human osteoblasts determined by two different techniques: (1) tritiated thymidine incorporation to DNA and (2) cell counting. Collagen synthesis by normal human osteoblasts showed a tendency to decrease following incubation with alendronate supplemented with fetal calf serum. This decrease was only statistically significant after 96 h of culture; however, a dose-response effect could not be documented. Finally, no effect of alendronate was observed on calcium deposition in vitro by normal human osteoblasts at concentrations equal to or lower than 10(-5) mol/L. In conclusion, the present study shows that alendronate in vitro does not affect viability, proliferation, and mineral deposit capacity of normal human osteoblasts at the concentration at which it inhibits by 50% the resorptive capacity of osteoclasts that for this drug has been reported as 2 x 10(-9) mol/L.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9580147&dopt=Abstract alendronate Fosamax