Fosamax scientific update |
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Biomaterials. 2007 Apr 20;
von Knoch F, Eckhardt C, Alabre CI, Schneider E, Rubash HE, Shanbhag AS.
Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA.
Anabolic effects of bisphosphonates on peri-implant bone stock.
The long-term durability of total joint replacements is critically dependent on adequate peri-implant bone stock, which can be compromised by wear
debris-mediated osteolysis. This study investigated the effects of bisphosphonates on enhancing peri-implant bone in the presence of clinically relevant
ultra-high molecular weight polyethylene (UHMWPE) wear debris. Fiber-mesh coated titanium-alloy plugs were implanted bilaterally in the femoral condyles of
36 New Zealand white rabbits. Implants in the left femora were covered with submicron UHMWPE particles during surgery. Rabbits were administered either no
drug, subcutaneous alendronate weekly (1.0mg/kg/week) or a single dose of intravenous zoledronate (0.015mg/kg). A total of 6/12 rabbits in each group were
sacrificed at 6 weeks and the remainder at 12 weeks postoperatively. Peri-implant bone stock was analyzed radiographically and histomorphometrically.
Radiographically, both bisphosphonates significantly increased periprosthetic cortical thickness at 6 weeks (p<0.0001; alendronate: +18%; zoledronate: +11%)
and at 12 weeks (p=0.001; alendronate: +17%; zoledronate:+19%). Histomorphometrically, alendronate and zoledronate raised peri-implant bone volume (BV/TV) up
to 2-fold after 6 weeks without added wear debris and more than 3-fold when wear debris was present. Furthermore a 6-week bisphosphonate treatment increased
osteoid thickness in the absence of wear debris (alendronate: +132%, p=0.007; zoledronate: +67%, p=0.51) and in the presence of wear debris (alendronate:
+134%, p=0.023; zoledronate: +138%, p=0.016). In summary, alendronate and zoledronate treatment increased periprosthetic bone stock in a rabbit femoral
model, particularly in the presence of UHMWPE wear debris. These new findings suggest that bisphosphonates may more than compensate for the well-documented
negative effects of wear debris on peri-implant bone stock. The combined antiresorptive and osteoanabolic effects of bisphosphonates on periprosthetic bone
stock may have an important role for critically improving the biological fixation and ultimate durability of total joint arthroplasty.
Ir Med J. 2007 Mar;100(3):410-1.
Khosa AD, Nayyar MS, Beirne JC.
Maxillofacial Unit, St James Hospital, Dublin.
Osteochemonecrosis of jaws and bisphosphonates.
Osteochemonecrosis of the jaws is a well described side effect of bisphosphonate therapy. Bisphosphonates are non metabolised analogues of pyrophosphate that
are capable of localizing to bone, slowing both rate of growth and rate of dissolution therefore reducing the rate of bone turnover. Although the exact
mechanism is not clear but it has been established that bisphosphonates target osteoclast, inhibiting their function in several ways: There are two types of
bisphosphonates. The first are oral preparations of bisphosphonates, which include Alendronate and Risedronate. They are indicated for the treatment of
osteoporosis. They are considered as lower risk of osteochemonecrosis. The second are administered intravenously. Pamindronate is a first generation
bisphosphonate; 90 mg administered intravenouly over 2-24 hours every 3-4 weeks. The next generation of intravenous bisphosphonate is Zoldronic acid, which
is more effective than Pamidronate in controlling hypercalcaemia of bone and reducing the skeletal related events in patients with metastatic breast cancer,
multiple myeloma, hypercalcaemia of malignancy, paget's disease and bone metastasis from prostate and lung cancer.
Ren Fail. 2007 May;29(4):471-476.
Yanik B, Bavbek N, Yanik T, Inegol I, Kanbay M, Turgut FH, Uz E, Akcay A.
School of Medicine, Physical Medicine and Rehabilitation, Fatih University. Ankara. Turkey.
The Effect of Alendronate, Risedronate, and Raloxifene on Renal Functions, Based on the Cockcroft and Gault Method, in Postmenopausal Women.
Background. Oral alendronate, risedronate, and raloxifene are effective treatment options in the management of postmenopausal osteoporosis. There is little
previously reported about the renal safety profiles of these three agents in osteoporosis. We aimed to assess the risk of renal toxicity associated with oral
alendronate, risedronate, and raloxifene in the treatment of osteoporosis, prospectively. Methods. One hundred and twenty-seven patients with osteoporosis
and osteopenia according to lumbar or femoral-neck bone mineral density t score were enrolled in the study. The patients were randomized to alendronate 70 mg
once weekly (n = 47), risedronate 35 mg once weekly (n = 44), or raloxifene 60 mg per day (n = 36) for one year. Preliminary screening included medical
history, physical examination, lumbar and femoral bone mineral densitometry measurement, and blood biochemical tests, including renal function tests. The
biochemical markers were then assessed at the end of 12 months. Results. There was no significant difference between basal and final renal function
parameters of each group. Also these parameters did not differ between the three groups after 12 months of treatment period. Conclusions. These results
demonstrate that alendronate, risedronate, and raloxifene are all safe drugs for renal functions in the treatment of osteoporosis.
J Bone Miner Res. 2006 Oct;21(10):1565-70.
Adami S, Isaia G, Luisetto G, Minisola S, Sinigaglia L, Gentilella R, Agnusdei D, Iori
ICARO Study Group
Fracture Incidence and Characterization in Patients on Osteoporosis Treatment: The ICARO
None of the available osteoporosis therapies have been shown to completely abolish the risk of
fractures. In clinical practice, the outcome may be even poorer. In 880 patients prescribed
with antiresorptives (alendronate, risedronate, and raloxifene) for >1 year, a fragility
fracture was recorded in 8.9%/year of them. This incidence is considerably higher than that
observed in randomized clinical trials, and it was significantly related to poor compliance
and lack of supplementation with calcium and vitamin D. Introduction: Osteoporotic fracture is
one of the most important public health concerns among the elderly. Currently available
therapies have been shown to significantly decrease the risk of fracture, although none of
them completely abolishes this risk. In clinical practice, poor treatment response may also
result from a number of other factors. Materials and Methods: The Incidence and
ChAracterization of inadequate clinical Responders in Osteoporosis (ICARO) is a multicenter,
observational study carried out in Italy. It aimed to analyze, in postmenopausal women with
established osteoporosis, the risk factors for an "inadequate clinical response" to drug
therapy, defined as the occurrence of new vertebral or nonvertebral fragility fractures in
patients prescribed, for at least 1 year, alendronate, risedronate, or raloxifene, with a
compliance >50%. Results: In 880 patients treated with antiresorptive agents for a median of
2.0 years (95% CI: 1.0-4.5) years, the "inadequate clinical responder (ICR)" subjects over the
observation period were 220 (25%), with an annual incidence of 8.9%. ICRs, compared with
"adequate clinical responders (ACRs)," had more pretreatment fractures and were treated longer
(2.8 versus 1.8 years; p < 0.001). After multiple adjustment for these confounding factors,
significant determinants of inadequate clinical response were a poorer treatment compliance
and a less frequent co-administration of calcium and vitamin D supplements. Conclusions: The
incidence of fractures during treatment with antiresorptive agents in a clinical setting is
considerably higher than that observed in randomized clinical trials. Inadequate compliance to
treatment and lack of supplementation of calcium and vitamin D are major determinants of this
poor response.
Endocr Regul. 2003 Dec;37(4):225-38.
Stepan JJ, Alenfeld F, Boivin G, Feyen JH, Lakatos P.
3rd Clinic of International Medicine, Charles University School of Medicine, Prague, Czech Republic.
Mechanisms of action of antiresorptive therapies of postmenopausal osteoporosis.
In the treatment of osteoporosis, the aim of the antiresorptive therapy is to restore bone density by decreasing bone remodeling. The process of bone remodeling plays a role in plasma calcium homeostasis and serves to modify bone architecture in order to meet changing mechanical needs, to maintain osteocyte viability, and to repair microdamage in bone matrix. Estrogen deficiency results in a number of detrimental effects on bone, including suppression of osteocyte survival as well as impairment of osteoblast response to mechanical stimuli and repair of ageing bone. In this review, effects of available antiresorptive therapies on endocrine regulations of bone metabolism in postmenopausal osteoporosis are compared. The aim of antiresorptive treatment is to ensure adequate bone remodeling, reparation of microdamage of bone, and increased bone strength. Ideally, this effect should be maintained long-term. Several agents are approved for the treatment of osteoporosis. Calcitonin transiently inhibits osteoclast activity without decreasing osteoblast collagen synthesis. Aminobisphosphonates decrease bone remodeling by decreasing osteoclast activity and by inducing osteoclast apoptosis. This allows more time for secondary mineralization to proceed to completion in the existing bone tissue mass, so increasing the mechanical resistance of bone to loading. Estrogens and raloxifene (a selective estrogen receptor modulator that acts as an estrogen agonist in bone) suppress bone remodeling to the premenopausal range, maintaining the function of osteoblasts and osteocytes. In the placebo-controlled osteoporosis treatment trials, all the above treatments reduced the risk of fractures. Raloxifene therapy was also associated with a favorable or neutral effect in the cardiovascular system, and a reduced incidence of breast cancer. Selection of appropriate drug for treatment of postmenopausal osteoporosis should take into account the long-term effect of the antiresorptive agent on bone. Moreover, the effects on other tissues ++should also be considered, and this encompasses both safety concerns, as well as the potentially beneficial effects on other tissues. Further investigation is needed to evaluate the different modes of action of these agents, and their long-term effects on bone and other tissues.
Obstet Gynecol Surv. 2004 Jun;59(6):446-55; quiz 485.
Kessel B.
Department of Obstetrics, Gynecology and Women's Health, University of Hawaii, John A. Burns School of Medicine, and The Queen's Medical Center, Honolulu, Hawaii 96813, USA.
Hip fracture prevention in postmenopausal women.
Hip fracture is a devastating outcome associated with postmenopausal osteoporosis. This fracture causes considerable pain, disability, diminished quality of life, and mortality. Although bone loss is an important factor associated with hip fracture, there are other demographic and clinical factors such as those that increase the risk of falling (e.g., unsteady gait, medications) that contribute to the likelihood of experiencing a hip fracture. Nonpharmacological interventions to reduce hip fracture risk include regular weight-bearing exercise, fall intervention programs, and external hip protectors. Patients should receive calcium and/or vitamin D supplementation as necessary. Among available pharmacologic options, the bisphosphonates, risedronate (Actonel) and alendronate (Fosamax), have reduced the risk of hip fracture in postmenopausal women with osteoporosis. Raloxifene (Evista), salmon calcitonin nasal spray (Miacalcin), and teriparatide (Forteo) have not demonstrated hip fracture risk reduction in controlled clinical trials. Hormone therapy (HT) reduced hip fracture risk in a recent large placebo-controlled trial; however, the risk/benefit profile of HT has resulted in recommendations to consider alternatives for the management of osteoporosis. Postmenopausal women with osteoporosis should receive adequate calcium/vitamin D supplementation, be encouraged to exercise, and institute risk factor interventions. Treatment with a bisphosphonate should be considered for those who are also at increased risk for hip fracture. TARGET AUDIENCE: Obstetricians & Gynecologyists, Family Physicians LEARNING OBJECTIVES: After completion of this article the reader should be able to list the demographic risk factors for osteoporosis and related fractures, to outline the cost and consequences of hip fractures, and to summarize the various pharmacologic and non-pharmacologic interventions used to reduce the risk of hip fracture.
J Periodontol. 2004 Dec;75(12):1579-85.
Rocha ML, Malacara JM, Sanchez-Marin FJ, Vazquez de la Torre CJ, Fajardo ME.
Institute of Medical Research, University of Guanajuato, Leon, Mexico.
Effect of alendronate on periodontal disease in postmenopausal women: a randomized placebo-controlled trial.
BACKGROUND: We investigated the effect of oral alendronate (ALN) treatment on radiological and clinical measurements of periodontal disease in postmenopausal women without hormone replacement therapy. METHODS: We evaluated the effect of 6 months of ALN treatment in 40 postmenopausal women, 55 to 65 years old with established periodontal disease, in a controlled, double-masked, prospective study. Volunteers were paired by age and randomized to receive ALN (10 mg/day) or placebo for the study period. Periodontal mechanical treatment was carried out in both groups. At baseline and after treatment, clinical evaluation, hormone blood levels, distance from the crestal alveolar bone (CAB) to the cemento-enamel junction (CEJ), calcaneus bone mineral density (BMD), hormone levels, serum N-telopeptide (NTx), and bone-specific alkaline phosphatase (BSAP) were assessed. RESULTS: Periodontal disease conditions improved in both groups, but greater improvement in probing depth (-0.8 +/- 0.3 mm versus -0.4 +/- 0.4 mm, P = 0.02) and gingival bleeding (-0.3% +/- 0.13% versus -0.2% +/- 0.06%, P = 0.006) was found in the ALN treated group. Calcaneus BMD increased in the ALN treated group (68 +/- 47 mm3 versus -26 +/- 81 mm3, P = 0.0006). CAB-CEJ distance diminished in the ALN group (-0.4 +/- 0.40 mm versus 0.60 +/- 0.53 mm, P = 0.00008). Marginal reduction in both NTx and BSAP levels was found in the ALN group (-9.4 +/- 6.6 nmol versus -4.3 +/- 4.7 nmol bone collagen equivalents, P = 0.08, and -7.7 +/- 8.4 versus -1.5 +/- 5.0 U/l, P = 0.1, respectively). Hormone levels were unchanged after treatment. Similar improvement of calcaneus BMD and CAB-CEJ distance with ALN treatment was found in obese and non-obese women. CONCLUSION: ALN treatment improved periodontal disease and bone turnover in postmenopausal women.
A systematic review of the effect of alendronate on bone mineral density in men.
Alendronate is known to increase bone mineral density (BMD) at the lumbar spine and hip in women, but less information is available in men. We conducted a systematic review of randomized controlled trials to determine whether oral alendronate improves BMD at the lumbar spine and hip in men with low bone mass or prevalent fractures, compared with men treated with placebo, calcium, or vitamin D. In three trials in men, BMD (measured by dual-energy X-ray absorptiometry) increased at 2-3 yr (compared to baseline) at the lumbar spine and femoral neck in alendronate-treated patients compared to controls. The pooled estimates of changes in BMD with 10 mg of alendronate daily compared to controls were as follows: 7.8% over 2-3 yr (95% confidence interval [CI] = 4.8- 10.8) at the lumbar spine and 3.8% (95% CI = 2.3-5.3) at the femoral neck (p < 0.001 for treatment effect in each analysis). Statistically significant heterogeneity of treatment effect was noted between trials. We conclude that 10 mg of oral daily alendronate is significantly associated with increase in BMD at the lumbar spine and hip in men over 2-3 yr and that these changes are similar to those previously observed in postmenopausal women.
Fosamax description...
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Drug category:Bone resorption inhibitor
 Fosamax scientific update
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