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Latest Research on Osteoporosis
     
Calcif Tissue Int. 2008 Jan 4 [Epub ahead of print]
Dietary Intake of Folate, but not Vitamin B(2) or B (12), Is Associated with Increased Bone Mineral Density 5 Years after the Menopause: Results from a 10-Year Follow-Up Study in Early Postmenopausal Women.
Rejnmark L, Vestergaard P, Hermann AP, Brot C, Eiken P, Mosekilde L.
The Osteoporosis Clinic, Department of Endocrinology and Metabolism C, Aarhus Sygehus, Aarhus University Hospital, Aarhus Sygehus, Tage-Hansens Gade 2, DK-8000, Aarhus C, Denmark, rejnmark@post6.tele.dk.

Folate, vitamin B(2) (riboflavin), and vitamin B(12 )may affect bone directly or through an effect on plasma homocysteine levels. Previously, a positive association has been found between plasma levels and bone mineral density (BMD) as well as risk of fracture. However, there are limited data on whether dietary intakes affect bone. Our aim was to investigate whether intake of folate, vitamin B(2,) and vitamin B(12), as assessed by food records affects BMD and fracture risk. In a population-based cohort including 1,869 perimenopausal women from the Danish Osteoporosis Prevention Study, associations between intakes and BMD were assessed at baseline and after 5 years of follow-up. Moreover, associations between intakes and 5- and 10-year changes in BMD as well as risk of fracture were studied. Intakes of folate, vitamin B(2), and vitamin B(12) were 417 (range 290-494) mug/day, 2.70 (range 1.70-3.16) mg/day, and 4.98 (range 3.83-6.62) mug/day, respectively, i.e., slightly above the intakes recommended by the United Nations Food and Agriculture Organization. At year 5, but not at baseline, cross-sectional analyses showed positive correlations between daily intake from diet and from diet plus supplements of folate and BMD at the femoral neck (P < 0.01). However, no associations were found between intakes and changes in BMD. During 10 years of follow-up, 360 subjects sustained a fracture. Compared with 1,440 controls, logistic regression analyses revealed no difference in intakes between cases and controls. A high dietary intake of folate, but not vitamin B(2) or B(12), exerts positive effects on BMD; but further studies are needed to confirm this association.

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J Nutr. 2008 Jan;138(1):172S-177S.
The balance of bone health: tipping the scales in favor of potassium-rich, bicarbonate-rich foods.
Lanham-New SA.
Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, Surrey, UK. s.lanham-new@surrey.ac.uk

Public health nutrition strategies to develop and maintain bone health throughout the lifecycle as well as to prevent osteoporosis in later life are urgently needed. In the United States, approximately 10 million Americans have osteoporosis, with costs estimated at $17.9 billion per year and costs in Europe well in excess of 13.9 billion euros. This review article outlines the current evidence available in the literature linking potassium-rich, bicarbonate-rich foods to osteoporosis prevention. The health-related benefits of a high intake of potassium-rich, bicarbonate-rich foods (e.g., fruits and vegetables) on disease prevention (e.g., cancer, heart disease) have been gaining increasing attention in the literature, and there is growing belief, from a variety of observational, experimental, clinical, and intervention studies, that a positive link exists between potassium-rich, bicarbonate-rich foods and indices of bone health. However, observational studies are not hypothesis proving and can only suggest the potential mechanisms of action. We now urgently need data from randomized controlled trials to determine for certain whether a potassium-rich, bicarbonate-rich diet or supplement is important to the skeleton. A 1-mo dietary intervention study involving 23- to 76-y-old men and women has shown that a diet high in bicarbonate (high fruits and vegetables) and potassium (high in milk and dairy products) (Dietary Approaches to Stopping Hypertension) significantly reduces bone turnover. Longer-term dietary studies are critical. In addition, the mechanisms underlying a positive effect of a potassium-rich, bicarbonate-rich diet on bone need to be fully determined. These currently include, but are not limited to, 1) the potential role of the skeleton in acid-base homeostasis; 2) other nutrient or dietary components found in abundance in fruits and vegetables such as vitamin K, beta-carotene, and vitamin C; and 3) other as yet "unidentified" dietary components. The road ahead is a challenging one.

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J Geriatr Phys Ther. 2007;30(2):79.
Effect of weighted exercises on bone mineral density in post menopausal women a systematic review.
Zehnacker C, Bemis-Dougherty A.
Physical Therapy Consults, Frederick, MD.

Purpose: Osteoporosis is both preventable and treatable with exercise playing an important role in osteogenesis. The purpose of this systematic review was to determine which specific exercise programs utilizing weights were effective in maintaining or increasing bone mineral density (BMD) in postmenopausal women. Methods: A computerized search of the MEDLINE, CINAHL, EMBASE, PEDro, and Science Citation databases was conducted for the period 1990 through February 2005. The search was performed using English language-only keyword searches using MESH terms osteoporosis, postmenopausal, exercise, weight training, and bone mineral density. A total of 20 articles was critically evaluated for the quality of an intervention study using the criteria developed by MacDermid. An expert on the topic was asked to review the list of articles for omissions. Results: The review revealed evidence to support the effectiveness of weight training exercises to increase BMD in postmenopausal women. The increases in BMD were site-specific and required high loading with a training intensity of 70% to 90% of 1 RM for 8 to 12 repetitions of 2 to 3 sets performed over one year duration. Conclusion: Weighted exercises can help in maintaining BMD in postmenopausal women and increasing BMD of the spine and hip in women with osteopenia and osteoporosis. The exercise program must be incorporated into a lifestyle change and be lifelong due to the chronic nature of bone loss in older women.

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South Med J. 2007 Dec;100(12):1214-8.
Reduced fracture rates observed only in patients with proper persistence and compliance with bisphosphonate therapies.
Silverman SL, Gold DT, Cramer JA.
Department of Medicine and Rheumatology, Cedars-Sinai Medical Center/UCLA, Beverly Hills, California 90211, USA. stuarts@slsdss.net

Numerous studies have analyzed data from administrative claims databases to determine persistence and compliance with bisphosphonate therapy for osteoporosis; several of these studies have also examined how persistence and compliance with therapy affect fracture outcomes. All of the studies included in this review demonstrated that patients who were persistent or compliant with therapy had a decreased risk of fracture. None, however, adequately addressed the question of what level of persistence or compliance is necessary to obtain a reduced risk of fracture. There is agreement among studies that compliance and persistence rates are suboptimal for all osteoporosis treatments. Measures to improve persistence and compliance with osteoporosis medications are needed if patients are to achieve the full clinical benefit of treatment.

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J Clin Endocrinol Metab. 2007 Dec 26 [Epub ahead of print]
Effects of Prior Antiresorptive Therapy on the Bone Mineral Density Response to Two Years of Teriparatide Treatment in Postmenopausal Women with Osteoporosis.
Boonen S, Marin F, Obermayer-Pietsch B, Simões ME, Barker C, Glass EV, Hadji P, Lyritis G, Oertel H, Nickelsen T, McCloskey EV; for the EUROFORS Investigators.
Leuven University Center for Metabolic Bone Diseases and Division of Geriatric Medicine, Universitaire Ziekenhuizen, Leuven, Belgium; Department of Medical Research, Lilly Research Center, Windlesham, United Kingdom; Universitätsklinik für Innere Medizin, Medizinische Universität, Graz, Austria; Instituto Portugues de Reumatologia, Lisbon, Portugal; Department of Endocrinology, Reproductive Medicine and Osteoporosis, Phillipps University, Marburg, Germany; Department of Orthopedics, University of Athens, Kifissia, Greece; The WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, Sheffield, United Kingdom.

Introduction- EUROFORS was a two-year prospective, randomized trial of postmenopausal women with established osteoporosis, designed to investigate various sequential treatments after teriparatide 20 microg/day for one year. The present secondary analysis examined the effects of two years of open-label teriparatide in women previously treated with antiresorptive drugs for at least one year. Methods- A subgroup of 245 women with osteoporosis who had two years of teriparatide treatment were stratified by prior predominant antiresorptive treatment into 4 groups: alendronate (n = 107), risedronate (n = 59), etidronate (n = 30), non-bisphosphonate (n = 49). Bone mineral density (BMD) at the lumbar spine and hip was determined after 6, 12, 18, and 24 months, and bone formation markers were measured after 1 and 6 months. Results- Significant increases in bone formation markers occurred in all groups after 1 month of teriparatide treatment. Lumbar spine BMD increased at all visits, while a transient decrease in hip BMD, that was subsequently reversed, was observed in all groups. BMD responses were similar in all prior antiresorptive groups. Prior etidronate users showed a higher increase at the spine but not at the hip BMD. Duration of prior antiresorptive therapy and lag time between stopping prior therapy and starting teriparatide did not affect the BMD response at any skeletal site. Treatment emergent adverse events were similar to those reported in treatment naïve postmenopausal women with osteoporosis treated with teriparatide. Conclusions- Teriparatide induces positive effects on BMD and markers of bone formation in postmenopausal women with established osteoporosis, regardless of prior long-term exposure to antiresorptive therapies.

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Osteoporos Int. 2007 Dec 18 [Epub ahead of print]
Monthly dosing of 75 mg risedronate on 2 consecutive days a month: efficacy and safety results.
Delmas PD, Benhamou CL, Man Z, Tlustochowicz W, Matzkin E, Eusebio R, Zanchetta J, Olszynski WP, Recker RR, McClung MR.
University of Lyon and INSERM Research Unit 831, Lyon, France.

Postmenopausal women with osteoporosis received 75 mg risedronate on two consecutive days each month or 5 mg daily for 12 months. Changes in bone mineral density and bone turnover markers were similar between treatments. Risedronate 75 mg twice monthly was effective and safe suggesting a new, convenient dosing schedule. INTRODUCTION: Patients perceive less frequent dosing as being more convenient. This 2-year trial evaluates the efficacy and safety of a new monthly oral regimen of risedronate; 1 year results are presented here. METHODS: Postmenopausal women with osteoporosis (n = 1229) were randomly assigned to double-blind treatment with 75 mg risedronate on two consecutive days each month (2CDM), or 5 mg daily. The primary endpoint was the percent change from baseline in lumbar spine (LS) bone mineral density (BMD) at month 12. Secondary efficacy was evaluated by mean percent changes from baseline in BMD in LS, total hip, trochanter, and femoral neck, and bone turnover markers (BTMs). RESULTS: Risedronate 75 mg 2CDM was non-inferior to 5 mg daily (treatment difference 0.21; 95% CI -0.19 to 0.62). Mean percent change in LS-BMD was 3.4% +/- 0.16 and 3.6% +/- 0.15 respectively. Mean percent changes in BMD and BTMs were significant and similar for both treatment groups. New vertebral fractures occurred in 1% of subjects with either treatment. Both treatments were generally well tolerated and safe. CONCLUSIONS: Risedronate 75 mg 2CDM was non-inferior in efficacy and did not show a difference in safety vs. 5 mg daily after 12 months, leading to a similar benefit.

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Ann Intern Med. 2007 Dec 17 [Epub ahead of print]
Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis.
Maclean C, Newberry S, Maglione M, McMahon M, Ranganath V, Suttorp M, Mojica W, Timmer M, Alexander A, McNamara M, Desai SB, Zhou A, Chen S, Carter J, Tringale C, Valentine D, Johnsen B, Grossman J.
the Southern California Evidence-based Practice Center, which includes RAND, Santa Monica.

BACKGROUND: Although several agents are available to treat osteoporosis, the relative efficacy and toxicity of these agents when used to prevent fractures has not been well described. PURPOSE: To compare the benefits in fracture reduction and the harms from adverse events of various therapies for osteoporosis. DATA SOURCES: MEDLINE (1966 to November 2007) and other selected databases were searched for English-language studies. STUDY SELECTION: For the efficacy analysis, investigators selected studies that reported the rate or risk for fractures. For the adverse event analysis, they selected studies that reported the relationship between an agent and cardiovascular, thromboembolic, or upper gastrointestinal events, malignant conditions, and osteonecrosis. DATA EXTRACTION: Using a standardized protocol, investigators abstracted data on fractures and adverse events, agents and comparators, study design, and variables of methodological quality. DATA SYNTHESIS: Good evidence suggests that alendronate, etidronate, ibandronate, risedronate, zoledronic acid, estrogen, parathyroid hormone (1-34), and raloxifene prevent vertebral fractures more than placebo; the evidence for calcitonin was fair. Good evidence suggests that alendronate, risedronate, and estrogen prevent hip fractures more than placebo; the evidence for zoledronic acid was fair. The effects of vitamin D varied with dose, analogue, and study population for both vertebral and hip fractures. Raloxifene, estrogen, and estrogen-progestin increased the risk for thromboembolic events, and etidronate increased the risk for esophageal ulcerations and gastrointestinal perforations, ulcerations, and bleeding. Limitation: Few direct comparisons have been conducted between different agents or classes of agents used to treat osteoporosis. CONCLUSION: Although good evidence suggests that many agents are effective in preventing osteoporotic fractures, data are insufficient to determine the relative efficacy or safety of these agents.

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Osteoporos Int. 2007 Sep 11; [Epub ahead of print]
Bone turnover and bone collagen maturation in osteoporosis: effects of antiresorptive therapies.
Byrjalsen I, Leeming DJ, Qvist P, Christiansen C, Karsdal MA.
Nordic Bioscience A/S, Herlev Hovedgade 207, Herlev, DK-2730, Denmark, ib@nordicbioscience.com.

Bone collagen maturation may be important for anti-fracture efficacy as the reduction in risk is only partly explained by a concomitant increase in BMD during anti-resorptive therapy. Different treatments caused diverse profiles in bone collagen degradation products, which may have implications for bone quality. INTRODUCTION: The aim of the present study was to evaluate the effect of different anti-resorptive treatments on bone collagen maturation measured as the ratio between the degradation products of newly synthesized and mature isomerized C-telopeptides of type I collagen. METHODS: Participants were from cohorts of healthy postmenopausal women participating in double blind, placebo-controlled 2-year studies of alendronate, ibandronate, intranasal hormone replacement therapy (HRT), oral HRT, transdermal HRT, or raloxifene (n = 427). The non-isomerized alphaalphaCTX and isomerized betabetaCTX were measured in urine samples obtained at baseline, and after 6, 12, and 24 months of therapy. RESULTS: Bone collagen maturation measured as the ratio between alphaalphaCTX and betabetaCTX showed that bisphosphonate treatment induced a collagen profile consistent with an older matrix with a 52% (alendronate) and 38% (ibandronate) reduction in the ratio between the two CTX isoforms vs. 3% and 15% with HRT or raloxifene, respectively. CONCLUSIONS: Anti-resorptive treatments had different effects on the endogenous profile of bone collagen maturation. Whether that effect on bone collagen has an impact on bone strength independent on the treatment-dependent effect on BMD should be investigated.

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J Am Med Dir Assoc. 2007 Sep;8(7):434-40.
Update on Osteoporosis Management in Long-term Care: Focus on Bisphosphonates.
Kamel HK.
Donald W. Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR.

Osteoporotic fractures are potentially devastating and associated with high morbidity and substantial economic burden. Residents of long-term care facilities are at greater risk of osteoporosis and its related fractures than those living in the community, yet osteoporosis is underdiagnosed and undertreated in these settings. Bisphosphonates are approved by the Food and Drug Administration for the treatment and prevention of osteoporosis in postmenopausal women. As a class, bisphosphonates have been shown to increase bone mineral density, decrease the markers of bone resorption, and reduce the risk of osteoporotic fractures. The 3 approved bisphosphonates are alendronate, risedronate, and ibandronate. Alendronate and risedronate are dosed daily or weekly and ibandronate, the most recently approved bisphosphonate, has been approved for monthly oral dosing or as an intravenous formulation to be given intermittently (every 3 months). In addition, other products with different mechanisms of action are in the pharmaceutical pipeline and may offer additional management options.

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Surg Neurol. 2007 Sep 5; [Epub ahead of print]
Bone health in patients with brain tumors.
Da Silva AN, Heras-Herzig A, Schiff D.
Division of Neuro-Oncology, Neurology Department, University of Virginia, Charlottesville, VA 22908, USA.

BACKGROUND: Several factors, including the use of antiepileptic drugs, glucocorticoids, anticoagulants, chemotherapy, radiation therapy, and hemiplegia-associated osteopenia, render patients with brain tumor susceptible to bone disease. METHODS: The authors review the pathophysiology of these factors and their impact upon bone integrity. RESULTS: Steps that can be taken to minimize or eliminate bone morbidity including measurement of bone mineral density at treatment onset, adequate calcium intake, vitamins D and K supplementation, adequate sunlight exposure, weight-bearing exercises, fall prevention, avoidance of antiepileptic drugs linked to osteopenia, and judicious use and choice of glucocorticoids and anticoagulants are suggested. CONCLUSIONS: Medical management of osteoporosis related to brain tumor treatment with bisphosphonates, teriparitide, and calcitonin is beneficial, as is kyphoplasty for symptomatic vertebral compression fractures.

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Am J Clin Nutr. 2007 Sep;86(3):781-9.
Changes in biochemical indexes of bone metabolism and bone mineral density after a 12-mo dietary intervention program: the Postmenopausal Health Study.
Manios Y, Moschonis G, Trovas G, Lyritis GP.
Department of Nutrition and Dietetics, Harokopio University, Athens, Greece and the Laboratory for the Research of the Musculoskeletal System, School of Medicine, University of Athens, Athens, Greece.

BACKGROUND: In southern Europe, calcium supplementation alone is a common practice for osteoporosis prevention. OBJECTIVE: We examined whether calcium supplementation could be as effective in achieving favorable bone mass changes in postmenopausal women as is a holistic dietary approach including dairy products fortified with calcium and vitamin D(3). DESIGN: A sample of 101 postmenopausal women were randomly assigned to a dairy intervention group (n = 39) who received daily approximately 1200 mg Ca and 7.5 mug vitamin D(3) via fortified dairy products and attended biweekly nutrition education sessions; a calcium-supplemented group (n = 26) who received a total of 1200 mg Ca/d; and a control group (n = 36). RESULTS: The increases observed in serum concentrations of insulin-like growth factor I were greater in the dairy intervention group than in the 2 other groups, especially during the first 5 mo of intervention (P = 0.034). The decreases and increases observed during 5 and 12 mo, respectively, in serum 25-hydroxyvitamin D(3) were significant in all groups (P = 0.050). Serum parathyroid hormone increased only in the control group, and serum type 1 collagen cross-linked C-telopeptide decreased only in the dairy intervention group during both 5 and 12 mo of intervention (P = 0.035 and 0.047, respectively). The dairy intervention group had greater improvements in pelvis (P = 0.040), total spine (P = 0.001), and total-body (P = 0.001) bone mineral density than did the other 2 groups. CONCLUSION: The application of a holistic intervention approach combining nutrition education and consumption of fortified dairy products for 12 mo can induce more favorable changes in biochemical indexes of bone metabolism and bone mineral density than can calcium supplementation alone.

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Am J Clin Nutr. 2007 Sep;86(3):639-44.
Effects of dietary calcium intake on body weight and prevalence of osteoporosis in early postmenopausal women.
Varenna M, Binelli L, Casari S, Zucchi F, Sinigaglia L.
Department of Rheumatology, Gaetano Pini Institute, University of Milan, Milan, Italy.

BACKGROUND: High calcium intakes seem to be ineffective at reducing bone loss in early postmenopausal women. However, the inverse relation between calcium intake and body weight can attenuate the negative effect of a low dietary calcium intake. OBJECTIVE: The objective was to assess the role of dietary calcium and body mass index (BMI) on osteoporosis, defined according to World Health Organization criteria as a lumbar bone density >2.5 SD below the T score. DESIGN: This was a cross-sectional, retrospective, observational study conducted in 1771 healthy, early postmenopausal women, who were not taking calcium supplements at the first densitometric evaluation. Weekly frequency of dairy food consumption was used to estimate the relative intake of dietary calcium. Total dairy intake was classified into 4 categories by quartile cutoffs. Multiple logistic regression analyses were used to study this sample. RESULTS: BMI and prevalence of overweight showed significant inverse trends
with increasing dairy intake. Calcium intake was not associated with osteoporosis when overweight was not considered. However, when overweight was considered in the analysis, women with the lowest calcium intake were more likely to have osteoporosis (odds ratio: 1.46; 95% CI: 1.12, 1.89; P = 0.008) than were women with the highest calcium intake. CONCLUSIONS: In early postmenopausal women, a low dietary calcium intake may increase the risk of osteoporosis, but its negative effect can be offset by the greater BMI found in women with a low calcium intake.

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Lancet. 2007 Aug 25;370(9588):657-66.
Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis.
Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A.
Centre for Complementary Medicine Research, University of Western Sydney, New South Wales, Australia. benjamin@clubsalsa.com.au

BACKGROUND: Whether calcium supplementation can reduce osteoporotic fractures is uncertain. We did a meta-analysis to include all the randomised trials in which calcium, or calcium in combination with vitamin D, was used to prevent fracture and osteoporotic bone loss. METHODS: We identified 29 randomised trials (n=63 897) using electronic databases, supplemented by a hand-search of reference lists, review articles, and conference abstracts. All randomised trials that recruited people aged 50 years or older were eligible. The main outcomes were fractures of all types and percentage change of bone-mineral density from baseline. Data were pooled by use of a random-effect model. FINDINGS: In trials that reported fracture as an outcome (17 trials, n=52 625), treatment was associated with a 12% risk reduction in fractures of all types (risk ratio 0.88, 95% CI 0.83-0.95; p=0.0004). In trials that reported bone-mineral density as an outcome (23 trials, n=41 419), the treatment was associated with a reduced rate of bone loss of 0.54% (0.35-0.73; p<0.0001) at the hip and 1.19% (0.76-1.61%; p<0.0001) in the spine. The fracture risk reduction was significantly greater (24%) in trials in which the compliance rate was high (p<0.0001). The treatment effect was better with calcium doses of 1200 mg or more than with doses less than 1200 mg (0.80 vs 0.94; p=0.006), and with vitamin D doses of 800 IU or more than with doses less than 800 IU (0.84 vs 0.87; p=0.03). INTERPRETATION: Evidence supports the use of calcium, or calcium in combination with vitamin D supplementation, in the preventive treatment of osteoporosis in people aged 50 years or older. For best therapeutic effect, we recommend minimum doses of 1200 mg of calcium, and 800 IU of vitamin D (for combined calcium plus vitamin D supplementation).

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Clin Breast Cancer. 2007 Jul;7 Suppl 1:S21-8.
Strategies for the prevention of treatment-related bone loss in women receiving adjuvant hormonal therapy.
Rugo HS.
Breast Oncology Clinical Trials Program, Comprehensive Cancer Center, University of California-San Francisco, 1600 Divisidero Street, San Francisco, CA 94115, USA. hrugo@medicine.ucsf.edu

More than 220,000 women will be diagnosed with breast cancer this year, and approximately 75% of these women will be long-term survivors of this disease. Survival has improved largely because of advances in adjuvant hormone therapy and chemotherapy, as well as early detection strategies. Because most women will receive adjuvant treatment, and the majority will survive cancer, it is increasingly important to understand the resultant toxicities and to devise monitoring and treatment strategies to avoid adverse long-term effects. Loss of bone mineral density leading to osteoporosis and increased risk of fracture as well as other morbidities is a well known complication of estrogen suppression associated with use of aromatase inhibitors (AIs) in postmenopausal women, and ovarian suppression with GnRH agonists or chemotherapy in premenopausal women. Hormone receptor positivity is increasingly frequent with increasing patient age, so that a large number of women already at risk for osteopenia associated with menopause are at risk for further bone loss caused by adjuvant hormone therapy with AIs. This article will review data on bone mineral density loss and risk of fracture in the large, randomized phase III trials comparing tamoxifen to AIs using the upfront, switching or extended hormone therapy approach. Data from prophylactic bisphosphonate intervention trials in both post- and premenopausal women will be discussed. Ongoing trials are described.

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Rev Med Liege. 2007 May-Jun;62(5-6):352-9.
[Advances in the treatment of postmenopausal osteoporosis]
[Article in French]
Reginster JY.
Service de Santé Publique, Epidémiologie et Economie de la Santé, ULg, CHU Sart Tilman, Liège. jyreginster@ulg.ac.be

During the last decade, several medications have been registered and marketed in osteoporosis. They have demonstrated their anti-fracture efficacy. Subsequently, the clinical management of osteoporosis becomes more sophisticated and complex. Bisphosphonates (alendronate, risedronate, ibandronate) have demonstrated their efficacy on the axial and appendicular skeleton. On scientific grounds, it seems difficult to distinguish between them, in terms of efficacy and/or safety. A special interest should be focused on the optimisation of patients' adherence, which remains poor with the daily and weekly formulations. Raloxifene, a selective estrogen receptor modulator, has shown anti-fracture efficacy at the level of the lumbar spine and, also, exerts collateral benefits on the breast. The peptides from the parathyroid hormone family are stimulators of bone formation. They showed anti-fracture efficacy at the axial and appendicular skeleton. Due to their prohibitive cost, their use should be restricted to patients with severe osteoporosis. Strontium ranelate, with its unique mode of action combining inhibition of bone resorption and stimulation of bone formation, is characterized by a wide scatter of activity, both in terms of skeletal sites positively affected and of patients experiencing benefits of its administration. Currently, it is the only drug which has shown an extensive anti-fracture efficacy in elderly subjects over 80 years old.

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Drug Saf. 2007;30(9):755-63.
Safety considerations with bisphosphonates for the treatment of osteoporosis.
Strampel W, Emkey R, Civitelli R.
Michigan State University College of Osteopathic Medicine, East Lansing, Michigan, USA.

Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Although evidence supports a good safety profile for these agents, numerous tolerability issues have been associated with their use. This review provides an overview of the safety issues associated with the nitrogen-containing class of bisphosphonates and discusses the potential effect of these issues on adherence. The review specifically considers upper gastrointestinal (UGI) adverse events (AEs), renal toxicity, influenza-like illness, osteonecrosis of the jaw and evidence on how to treat or prevent these events.In clinical trials, UGI AEs, including severe events such as oesophageal ulcer, oesophagitis and erosive oesophagitis, have been reported at similar frequencies in placebo- and active-treatment arms. However, postmarketing studies have highlighted UGI AEs as a concern. These studies show that a significant portion of patients are less compliant with administration instructions outside strict clinical trial supervision, and when oral bisphosphonates are not administered as directed, patients are more likely to experience UGI AEs. Some clinical trials with oral bisphosphonates have suggested that a decrease in the frequency of administration may lead to improvement in gastrointestinal tolerability. In the authors' experience, the issue of UGI tolerability can be minimised by explaining to the patient and/or caregiver the importance of following administration instructions.Intravenous (IV) bisphosphonates have been recently approved for use in osteoporosis, offering an alternative regimen for patients with osteoporosis. Earlier generation IV bisphosphonates (e.g. etidronate) have been associated with acute renal failure. Alternatively, late-generation IV bisphosphonates (i.e. ibandronate) have shown a better safety profile in relation to renal toxicity.Influenza-like illness, often referred to as an acute-phase reaction, covers symptoms such as fatigue, fever, chills, myalgia and arthralgia. These symptoms are transitory and self-limiting and usually do not recur after subsequent drug administration. Symptoms of influenza-like illness have been associated with both IV and oral bisphosphonates. Osteonecrosis of the jaw has also been associated with IV bisphosphonate treatment, particularly in patients treated with high doses. A small number of patients with cancer and osteoporosis using oral bisphosphonates have also reported this AE. As osteonecrosis of the jaw is difficult to treat and is often associated with dental procedures and poor oral hygiene, preventive measures seem to be the best management option for patients taking bisphosphonates. Overall, the safety and tolerability profile of the nitrogen-containing bisphosphonates is good, and long-term treatment does not appear to carry a risk of serious AEs. By encouraging adherence to administration instructions physicians can minimise certain complications, such as UGI intolerability. By being aware of other potential safety issues, such as renal impairment, influenza-like illness and osteonecrosis of the jaw, physicians can detect these AEs early in the course of treatment.

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Menopause. 2007 May-Jun;14(3 Suppl):567-71.
Effect of early menopause on bone mineral density and fractures.
Gallagher JC.
>From the Creighton University Medical Center, Omaha, NE.

OBJECTIVE:: To review the data on the effect of early menopause on bone. Do women undergoing early menopause develop lower bone mineral density at an earlier age and do they have a higher incidence of osteoporotic fractures? Is there a difference on bone between women who undergo early natural menopause compared to women who have early menopause after oophorectomy? RESULTS:: The earlier in life that menopause occurs, the lower the bone density will be later in life. Low bone density is associated with a higher fracture rate, and several studies show a relationship between early menopause, oophorectomy, and an increase in osteoporotic fractures. CONCLUSIONS:: Early menopause is a risk factor for osteoporosis. Women with an early menopause should have bone density testing performed within 10 years of menopause so that osteopenia or osteoporosis will be diagnosed early and appropriate antiresorptive therapy initiated.

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Orthopade. 2007 May 4; [Epub ahead of print]
[Transient osteoporosis and osteonecrosis of the femoral head : Risk factors, classification and differential diagnosis.]
[Article in German]
Rader CP.
St. Franziskus-Hospital, Schonsteinstrasse 63, 50825, Koln-Ehrenfeld, Deutschland, c.rader@st-franziskus-koeln.de.

Osteonecrosis of the femoral head usually affects patients in their third to fifth decade of life. Common risk factors are alcohol, nicotine, corticosteroids, hyperlipidaemia and hypercoagulability. Depending on the stage of the osteonecrosis, the diagnosis is confirmed by radiographs, magnetic resonance imaging or scintigraphy. The ARCO classification (Association Research Circulation Osseous), which is based on older classifications recommended by Ficat/Arlet, Steinberg, Koo or Marcus/Enneking, is a valuable prognostic tool for finding an adequate treatment option.Transient osteoporosis of the hip is controversially discussed as a pre-stage of osteonecrosis or a self-limiting condition based on reflex dystrophy. Conservative and operative treatment options are reported in the literature. Recently published data favour core decompression as an effective procedure for early stage osteonecrosis and transient osteoporosis.

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N Engl J Med. 2007 May 3;356(18):1809-22. Comment in: N Engl J Med. 2007 May 3;356(18):1878-80. N Engl J Med. 2007 May 3;356(18:1895-6.
Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis.
Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR; HORIZON Pivotal Fracture Trial.
University of California, San Francisco, San Francisco, CA 94107, USA. dblack@psg.ucsf.edu

BACKGROUND: A single infusion of intravenous zoledronic acid decreases bone turnover and improves bone density at 12 months in postmenopausal women with osteoporosis. We assessed the effects of annual infusions of zoledronic acid on fracture risk during a 3-year period. METHODS: In this double-blind, placebo-controlled trial, 3889 patients (mean age, 73 years) were randomly assigned to receive a single 15-minute infusion of zoledronic acid (5 mg) and 3876 were assigned to receive placebo at baseline, at 12 months, and at 24 months; the patients were followed until 36 months. Primary end points were new vertebral fracture (in patients not taking concomitant osteoporosis medications) and hip fracture (in all patients). Secondary end points included bone mineral density, bone turnover markers, and safety outcomes. RESULTS: Treatment with zoledronic acid reduced the risk of morphometric vertebral fracture by 70% during a 3-year period, as compared with placebo (3.3% in the zoledronic-acid group vs. 10.9% in the placebo group; relative risk, 0.30; 95% confidence interval [CI], 0.24 to 0.38) and reduced the risk of hip fracture by 41% (1.4% in the zoledronic-acid group vs. 2.5% in the placebo group; hazard ratio, 0.59; 95% CI, 0.42 to 0.83). Nonvertebral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25%, 33%, and 77%, respectively (P<0.001 for all comparisons). Zoledronic acid was also associated with a significant improvement in bone mineral density and bone metabolism markers. Adverse events, including change in renal function, were similar in the two study groups. However, serious atrial fibrillation occurred more frequently in the zoledronic acid group (in 50 vs. 20 patients, P<0.001). CONCLUSIONS: A once-yearly infusion of zoledronic acid during a 3-year period significantly reduced the risk of vertebral, hip, and other fractures. (ClinicalTrials.gov number, NCT00049829.) Copyright 2007 Massachusetts Medical Society.

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Urologe A. 2007 Apr 24; [Epub ahead of print]
[Prevention of osteoporosis—important for the urologist?]
[Article in German]
Lummen G, Rubben H, Schneider T, Sperling H.
Klinik fur Urologie, Kinderurologie und Uroonkologie, St. Josef-Hospital, Hospitalstrasse 45, 53840, Troisdorf, Deutschland, dr.gerd.luemmen@josef-hospital.de.

Osteoporosis is a systemic disease of the bones with increasing incidence in the elderly. Over the age of 50 years bone mineral density continuously decreases resulting in osteoporotic fracture. Osteoporosis is positively correlated with late-onset hypogonadism and increases under androgen deprivation therapy.The evaluation of osteoporosis should be done in cooperation with an endocrinologist. Measurement of bone mineral density is recommended before starting androgen deprivation therapy. Patients with fracture and/or decreased bone mineral density 2.5 or more standard deviations below normal peak bone mass of young men should be treated. The appropriate treatment is calcium and vitamin D substitution combined with oral or i.v. administration of bisphosphonates.

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Cochrane Database Syst Rev. 2007 Apr 18;(2):CD005645.
Interventions for the treatment of decreased bone mineral density associated with HIV infection.
Lin D, Rieder M.

BACKGROUND: Decreased bone mineral density (BMD) occurs more commonly in patients with HIV than in the general population, making this group more susceptible to fragility fractures. However, bone loss is under-treated in patients with HIV. OBJECTIVES: To assess the effects of interventions aimed at increasing bone mineral density in HIV-infected adults. SEARCH STRATEGY: We searched MEDLINE, EMBASE, LILACS, The Cochrane Library, Meeting Abstracts, AIDSTRIALS, ACTIS, Current Controlled Trials, National Institutes of Health Clinical Trials Registry, and CenterWatch (search date July 2006). SELECTION CRITERIA: Randomised trials comparing any pharmacological or non-pharmacological therapy with placebo, no treatment, or an alternative therapy, with the goal of increasing bone mineral density in adult (age 18 years or over) patients with HIV. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial eligibility and quality, and extracted data. Where data were incomplete or unclear, conflicts were resolved with discussion and/or trial authors were contacted for further details. MAIN RESULTS: Three completed randomised-controlled studies examined the role of alendronate in patients with HIV and osteopenia or osteoporosis. When all three studies were combined, much heterogeneity was seen (p<0.0001), most likely due to different populations and interventions. A sensitivity analysis showed that in two studies without heterogeneity (p=0.11), alendronate, calcium and vitamin D improved lumbar BMD after one year when compared with calcium and vitamin D (weighted mean difference +2.65 95% confidence interval (CI) 0.80, 4.51 percent). However the alendronate group did not have less fragility fractures, relative risk (RR) 1.28 (95% CI 0.20, 8.21), or osteoporosis, RR 0.50 (95% CI 0.24, 1.01). Adverse events were not significantly different between groups, RR 1.28 (95% 0.20, 8.21). One randomised-controlled study done in patients with AIDS wasting found that after three months, testosterone enanthane improved lumbar BMD compared to placebo by +3.70 (95% CI 0.48, 6.92) percent, but progressive resistance training did not improve lumbar BMD (+0.40 95% CI -2.81, 3.61 percent). No group in this study had any adverse effects. AUTHORS' CONCLUSIONS: The very limited data reviewed showed that bisphosphonate therapy andin those with AIDS wasting syndrome, testosteronemay be safe and possibly effective methods to improve bone mineral density in HIV patients. The available studies are small, of short duration, and not powered to detect changes in WHO categories and fracture rates.Larger studies using bisphosphonates are currently underway. The role of colecalciferol, androgen replacement in women, and growth hormone are also under investigation.

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J Clin Endocrinol Metab. 2007 Apr 17; [Epub ahead of print]
Addition of monofluorophosphate to estrogen therapy in postmenopausal osteoporosis—a randomized controlled trial.
Reid IR, Cundy T, Grey AB, Horne A, Clearwater J, Ames R, Orr-Walker BJ, Wu F, Evans MC, Gamble GD, King A.
Department of Medicine, University of Auckland, Auckland, New Zealand; Pathology Laboratory, Middlemore Hospital, Auckland, New Zealand.

Introduction: Treatment of osteoporosis with high-dose fluoride alone does not reduce fracture risk. We hypothesized that the anti-fracture efficacy of fluoride could be optimized by its use in low doses combined with an antiresorptive agent. Experimental Subjects: 80 women with postmenopausal osteoporosis who had been taking estrogen for >/=1 year. Methods: Subjects were randomized to receive monofluorophosphate (fluoride content of 20 mg/day) or placebo over 4 years in a double-blind trial. Results and Discussion: There were progressive increases in lumbar spine bone density (BMD) over the duration of the study (MFP 22%, placebo 6%, P<0.0001). In the trabecular bone of L3, these increases were even greater (MFP 49%, placebo 2.5%, P<0.0001). In the proximal femur there were smaller but significant treatment effects (P=0.015). Total body scans and their subregions also showed significantly greater increases in the MFP group. Bone formation markers increased significantly in the MFP group at year 1. Hyperosteoidosis was present in biopsies from 5 of 7 MFP subjects, with osteomalacia in 2 of 7. The hazards ratio for vertebral fractures was 0.20 (95% confidence interval 0.05-1.30) and the incidence rate ratio was 0.12 (95% confidence interval, 0.06-0.23, P<0.01). The hazards ratio for non-vertebral fractures was 3.3 (95% CI 0.8-12.0). We conclude that fluoride 20 mg/day produces substantial increases in BMD, but still interferes with bone mineralization. This indicates that most previous studies with this ion have used toxic doses, and that much lower doses should be assessed to find a safe dose window for the use of this powerful anabolic agent.

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Panminerva Med. 2007 Mar;49(1):21-7.
Osteoporotic fractures: mortality and quality of life.
Caliri A, De Filippis L, Bagnato GL, Bagnato GF.
Unit of Rheumatology, Department of Internal Medicine, G. Martino Hospital, Messina, Italy.

Osteoporosis is a widespread disease, affecting about 75 million people, mostly postmenopausal women. It is called ''the silent disease'', since there are very few associated symptoms: anyway osteoporotic fractures are the chief clinical feature, with an enormous burden on health related quality of life and mortality. The aim of this study was to review the literature on the evaluation of mortality and health related quality of life as consequences of osteoporotic fractures. Fractures, the clinical manifestation of osteoporosis, are extremely common and are devastating both to affected patients and to society that must bear the enormous cost of fracture treatment and subsequent disability. Hip and spine fractures are linked with increased mortality, and all fractures may lead to disability and reduced quality of life. Since patients with osteoporosis usually have no symptoms before fracture, early diagnosis and treatment of the disease are of great importance to the quality of life in these patients. To reduce mortality, attention must focus on optimising health status preoperatively, preventing postoperative complications, and, when these complications develop, providing optimal specialist medical care.

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Bone. 2007 Mar 24; [Epub ahead of print]
Intravenous zoledronic acid 5 mg in the treatment of postmenopausal women with low bone density previously treated with alendronate.
McClung M, Recker R, Miller P, Fiske D, Minkoff J, Kriegman A, Zhou W, Adera M, Davis J.
Oregon Osteoporosis Center, 5050 NE, Hoyt Street, Ste 651, Portland, OR 97213-2954, USA.

This randomized, double-blind, double-dummy, multicenter trial assessed safety and efficacy of a single dose of IV zoledronic acid (ZOL) 5 mg vs. oral alendronate (ALN) 70 mg weekly in postmenopausal women with low bone mineral density (BMD) who had previously been treated with ALN. Postmenopausal women who were receiving oral ALN for at least 1 year immediately prior to randomization and with lumbar spine or femoral neck BMD T-score values </= -2.0 prior to initiation of ALN were randomized to one 15-min IV infusion of ZOL 5 mg plus 52 weeks of oral placebo (n=113) or one IV infusion of placebo plus 52 weeks of oral ALN 70 mg (n=112). End points included percent change in lumbar spine BMD from baseline to month 12 and relative change from baseline in urine N-telopeptide of type I collagen (NTX), serum C-telopeptide of type I collagen (CTX), amino terminal propeptides of type I collagen (PINP), and bone-specific alkaline phosphatase (bone ALP) over 12 months. Adverse events, bone histomorphometry and microscopic appearance, and patient preference for the 2 treatment regimens were also assessed. In this study, a single infusion of ZOL 5 mg maintained BMD 12 months following the switch from oral ALN in women with osteoporosis. The mean duration of prior ALN therapy at baseline was 4 years. Mean biomarker levels in the ALN 70-mg group remained at or close to baseline levels for the duration of the study. In the ZOL 5-mg group, mean biomarker levels were reduced from baseline after 3 months, returned to baseline after 6 months, and increased thereafter but remained within the premenopausal range. The overall rates of adverse events were comparable in the 2 groups (ZOL 5 mg, 86.7%; ALN 70 mg, 80.4%). Headache occurred more commonly within the first 3 days after infusion with ZOL 5 mg (12.4%) than with ALN 70 mg (6.3%). Bone biopsies indicate that both treatments decrease excessive remodeling seen in osteoporosis. The majority (78.7%) of patients expressed preference for once yearly infusion over weekly oral therapy. We conclude that patients can be switched from oral ALN to ZOL 5 mg infusion with maintenance of therapeutic effect for at least 12 months and that patients prefer a once yearly infusion to weekly oral therapy.

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Menopause Int. 2007 Mar;13(1):35-7.
Calcium and vitamin D—for whom and when.
Prince RL.
School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia; Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Western Australia.

The basis of 'nutritional' interventions for the prevention of postmenopausal osteoporosis and osteoporotic fracture is a large topic with much genetic and biochemical evidence, as well as the results of randomized controlled trials, to guide the investigator and clinician. The efficacy of treatment with calcium and vitamin D was once controversial, but with the advent of controlled clinical trials using bone mineral density as an endpoint it has become clear that calcium with or without vitamin D therapy can lead to reductions in the rate of bone loss in postmenopausal women of all ages. Furthermore, with certain caveats, calcium with vitamin D therapy in the older postmenopausal woman can lead to useful reductions infracture rates and falls, especially in populations with reduced exposure to sunlight, which is potentially the majority of postmenopausal women in both developed and developing countries. However, estrogen, selective estrogen receptor modulators (SERMs) and bisphosphonates (especially when given in combination with calcium and vitamin D) are more efficacious in preventing fracture, particularly in postmenopausal patients with impaired bone structure.

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Eur J Intern Med. 2007 Jan;18(1):6-17.
The diagnosis and treatment of male osteoporosis: Defining, assessing, and preventing skeletal fragility in men.
Boonen S, Kaufman JM, Goemaere S, Bouillon R, Vanderschueren D.
Leuven University Center for Metabolic Bone Diseases, Katholieke Universiteit Leuven, Leuven, Belgium; The Leuven University Department of Geriatric Medicine, Katholieke Universiteit Leuven, Leuven, Belgium; The Leuven University Laboratory for Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.

Male osteoporosis is associated with a significant burden in terms of morbidity, mortality, and economic cost. Despite recent advances in the understanding of the male osteoporotic syndrome, the evaluation and treatment of men suffering from osteoporosis remains a clinical challenge. In men with osteoporosis, it remains particularly critical to exclude underlying pathological causes as these are much more likely to be present than in women. There is increasing evidence that the approaches developed to diagnose and treat the disorder in women may be equally useful in men. The available evidence suggests that the anti-fracture efficacy of treatment with alendronate, risedronate, or teriparatide is similar in both sexes. Additional research is warranted to prospectively address the usefulness of BMD measurements to predict fracture risk, to identify those men who are likely to benefit the most from therapy, and to monitor individual responses to therapy.

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Drugs Aging. 2007;24(1):37-55.
Patient adherence to osteoporosis medications : problems, consequences and management strategies.
Papaioannou A, Kennedy CC, Dolovich L, Lau E, Adachi JD.
Department of Medicine, McMaster University, Hamilton, Ontario, CanadaThe Team for Individualizing Pharmacotherapy in Primary Care for Senior (TIPPS), Hamilton, Ontario, Canada.

Adherence to osteoporosis medications is relatively poor. Approximately 20-30% of patients taking daily or weekly treatments may suspend their treatment within 6 to 12 months of initiating therapy. Patients with poor adherence increase their risk of osteoporotic fractures and hospitalisation. The majority of patients who discontinue therapy appear to do so because of drug-induced adverse effects. Fear of adverse effects or other health risks is another commonly cited reason for discontinuing therapy. Factors associated with medication adherence include fractures, regular exercise, female sex, fewer non-osteoporosis medications and co-morbidities, early menopause, willingness to take medications, awareness of osteoporosis status based on a diagnostic test, anti-inflammatory therapy and corticosteroid therapy. Factors associated with non-adherence include adverse effects, pain and being unsure about bone mineral density (BMD) test results. Bisphosphonates, a common class of drugs for treating osteoporosis, have specific administration requirements (e.g. fasting, remaining upright and not ingesting other medications concomitantly). Patient surveys indicate that 12-18% of patients report non-compliance with at least one administration rule. Strategies to increase adherence include reducing administration frequency to weekly or monthly, monitoring patients with bone markers and BMD testing, providing adequate instructions, practitioner feedback and support, and educational materials and sessions. Future studies are needed regarding strategies to increase adherence to osteoporosis medications.

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Rheumatol Int. 2007 Jan 11; [Epub ahead of print]
Superiority of a combined treatment of Alendronate and Alfacalcidol compared to the combination of Alendronate and plain vitamin D or Alfacalcidol alone in established postmenopausal or male osteoporosis (AAC-Trial).
Ringe JD, Farahmand P, Schacht E, Rozehnal A.
Medical Clinic 4, Leverkusen Clinic (University of Cologne), Leverkusen, Germany, ringe@klinikum-lev.de.

A combined therapy with the strongly antiresorptive Alendronate and the pleiotropically acting D-hormone analogue Alfacalcidol may have additive effects on bone quality, falls and fracture risk in established osteoporosis. The aim of this study (Alfacalcidol Alendronate Combined-AAC) was to compare the efficacy and safety of a combined parallel therapy with Alendronate and Alfacalcidol to the treatment with either Alendronate in combination with plain vitamin D or Alfacalcidol alone in patients with established postmenopausal or male osteoporosis. Ninety patients were included as matched triplets to receive randomly either 1 mug Alfacalcidol daily + 500 mg calcium (group A, n = 30) or 70 mg Alendronate weekly + 1,000 mg calcium + 1,000 IU vitamin D daily (group B, n = 30) or 1 mug Alfacalcidol daily + 70 mg Alendronate weekly + 500 mg calcium daily (group C, n = 30). Patients were recruited in one centre and were followed up for 24 months. Analysis was intention-to-treat and the primary outcome was lumbar spine and total hip bone mineral density (measured observer blind). BMD was measured at the lumbar spine and at the proximal femur with dual energy X-ray absorptiometry (LUNAR Prodigy, GE, USA) at the beginning and after 12 and 24 months. During the 2-year-study we observed descriptively significant increases at the lumbar spine of 3.0% in group A compared to baseline, of 5.4% in group B and of 9.6% in group C, respectively. The superiority of the Alendronate + Alfacalcidol treatment group over Alfacalcidol alone and over Alendronate + vitamin D was of more than large relevance (both tests: MW > 0.71; CI-LB > 0.64; P < 0.001). We also observed median increases of the BMD at the total hip of 1.5% in group A, of 2.4% in group B and of 3.8% in group C, respectively. The superiority of group C over group A and over group B again was relevant and statistically significant in a descriptive sense. After 2 years there was a tendency towards higher rates of vertebral and non-vertebral fractures in group A and B as compared to C. Taking both fracture types together we observed 9, 10 and 2 "osteoporotic fractures" in groups A, B and C, respectively. The comparison of group C with pooled groups A and B and with each single group gave a relevantly lower fracture rate for the combination of Alendronate and Alfacalcidol. Furthermore a lower rate of falls was observed for the combination Alendronate plus Alfacalcidol versus Alendronate + vitamin D, but not versus Alfacalcidol alone. We found 80% of the patients in the Alendronate + Alfacalcidol group free from back pain at month 24, compared to 30% in the Alendronate + vitamin D and 43% in the Alfacalcidol monotherapy group. The superiority is relevant (both tests: MW > 0.64; CI-LB > 0.56; P < 0.003). Pain decrease also occurred more rapidly in the Alendronate + Alfacalcidol group than in the other groups. In general side effects in all groups were mild, and only four cases of moderate hypercalcuria in group A and one in group C were reported, but no case of hypercalcemia was documented. In conclusion, the combination therapy with Alendronate and Alfacalcidol exhibited superiority in terms of BMD, overall fractures, rate of falls and back pain over either Alendronate in combination with plain vitamin D or Alfacalcidol alone. The overall safety profiles of the three treatment regimens were found to be not different in this study.

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BMC Musculoskelet Disord. 2007 Jan 10;8(1):3 [Epub ahead of print]
The impact of vitamin D status on changes in bone mineral density during treatment with bisphosphonates and after discontinuation following long-term use in post-menopausal osteoporosis.
Deane A, Constancio L, Fogelman I, Hampson G.
Full free text at: http://www.biomedcentral.com/content/pdf/1471-2474-8-3.pdf

ABSTRACT: BACKGROUND: It is still unclear whether addition of calcium/vitamin D supplements leads to an incremental benefit in patients taking bisphosphonates and whether achievement of serum level of 25 (OH) vitamin D of at least 70 nmol/L has an impact on the skeletal response to bisphosphonates. Moreover the maintenance of BMD after bisphosphonates withdrawal with the continuation of calcium/vitamin D supplements only, remains uncertain. The aims were to assess the impact of vitamin D status on changes in bone mineral density (BMD) in firstly patients with post-menopausal osteoporosis on bisphosphonates and secondly following discontinuation of bisphosphonates after long-term use. METHODS: Two patient groups were recruited. The first study population comprised of 112 women treated with a bisphosphonate. The second study population consisted of 35 women who had been on bisphosphonates for > 5 years in whom the treatment agent was discontinued. Baseline BMD, changes in BMD following treatment, duration of treatment, serum 25 (OH) vitamin D, parathyroid hormone (PTH), urine C-terminal telopeptides of type 1 collagen (CTX) were obtained on all study participants. RESULTS: In the first study group (n =112), subjects with serum vitamin D concentrations (> 70 nmol/L) had a significantly lower serum PTH level (mean [SEM] 41 [2] ng/L ). PTH concentrations of 41 ng/L or less was associated with a significantly higher increase in BMD at the hip following treatment with bisphosphonates compared to patients with PTH > 41 ng/L (2.5% [ 0.9] v/s -0.2% [0.9], P = 0.04). In the second study group (n = 35), discontinuation of bisphosphonate for 15 months after long-term treatment did not result in significant bone loss at the lumbar spine and total hip, although a trend towards gradual decline in BMD at the femoral neck was observed. CONCLUSIONS: optimal 25 (OH) vitamin D concentration prevents bone loss at the hip in patients on bisphosphonates. A prospective controlled trial is needed to further evaluate whether the response to bisphosphonates is influenced by vitamin D status. BMD is preserved at the lumbar spine and total hip following discontinuation of bisphosphonate for a short period following long-term treatment, although a gradual loss occurs at the femoral neck.

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Joint Bone Spine. 2006 Dec 4; [Epub ahead of print]
How long should patients take medications for postmenopausal osteoporosis?
Briot K, Tremollieres F, Thomas T, Roux C; pour le comite scientifique du GRIO.
Rheumatology Department, Paris-Descartes University, School of Medecine; Assistance Publique-Hopitaux de Paris, Cochin Teaching Hospital, 27 rue du Faubourg Saint Jacques, 75014 Paris, France.

Several medications have proved effective in reducing the fracture risk in postmenopausal women with osteoporosis. The optimal duration of use of these medications remains to be established, however. Gains in bone mineral density (BMD) persisted throughout 10years of treatment with alendronate or 7years with risedronate. However, proof of long-term protection against fractures was obtained only for shorter treatment periods, 4years with alendronate and 5years with risedronate. The persistence of treatment effects after drug discontinuation varies across medications, and further studies are needed before this point can be incorporated into treatment decisions. With raloxifene, the BMD effect observed after 3 and 4years persisted when the drug was given for 8years, and the fracture risk reduction was similar after 4years and after 3years. The long-term safety profile also was similar, with a significant decrease in the incidence of invasive estrogen-receptor-positive breast cancer and a persistent increase in the risk of deep vein thrombosis. However, a sharp drop in BMD occurred upon raloxifene discontinuation. Thus, 4years may be appropriate for anti-resorptive drug therapy. However, the optimal treatment duration should be determined on a case-by-case basis according to the results of regular fracture-risk evaluations.

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Joint Bone Spine. 2006 Nov 28; [Epub ahead of print]
Effects of osteoporosis medications on bone quality.
Benhamou CL.
CHR Orleans, Service de Rhumatologie, Unite INSERM U 658, 1 rue Porte Madeleine, BP 2439, 45032 Orleans Cedex 1, France.

In clinical practice, the quantitative evaluation of bone tissue relies on dual-energy X-ray absorptiometry (DXA) measurements of bone mineral density (BMD) values, which are closely associated with the risk of osteoporotic fracture. However, only a small fraction of the antifracture effect of bone resorption inhibitors is ascribable to BMD gains (4% with raloxifene and 16-28% with alendronate and risedronate). Bone quality encompasses a number of bone tissue properties that govern mechanical resistance, such as bone geometry, cortical properties, trabecular microarchitecture, bone tissue mineralization, quality of collagen and bone apatite crystal, and presence of microcracks. All these properties are dependent on bone turnover and its variations. In populations, the decreases in bone resorption markers achieved with resorption inhibitors may predict in part the decrease in fracture risk. At the spine, however, this correlation exists down to a 40% fall in bone resorption markers; larger drops did not provide further protection against fractures in patients taking risedronate in one evaluation of this relationship. Osteoporosis medications can exert favorable effects on bone size and cortical thickness. Such effects have been documented with teriparatide (PTH 1-34), which is the unique purely anabolic treatment for osteoporosis available to date. More surprising are the favorable effects on bone size seen with some of the bone resorption inhibitors such as neridronate in adults with osteogenesis imperfecta. Similarly, estrogens and alendronate can increase femoral neck size in postmenopausal women. Preservation of the trabecular microarchitecture was demonstrated first with risedronate and subsequently with alendronate. In placebo-controlled studies, a deterioration in trabecular microarchitecture occurred within 1 to 3years in the placebo groups but not in the bisphosphonate groups. Teriparatide, in contrast, improves trabecular microarchitecture, in particular by increasing connectivity and improving the plate-rod distribution. The minerals within trabecular or cortical bone can be evaluated using microradiography or synchrotron micro-computed tomography. Marked or prolonged secondary mineralization may result in poor bone quality. Increased bone mineralization is among the key effects of bone resorption inhibitors, most notably bisphosphonates. Prolonged use of the most potent bisphosphonates may lead to unwanted effects related to excessive mineralization. Microcracks may play a physiological role; however, a large number of microcracks may be deleterious via an effect on osteocytes. Excessive mineralization may promote the development of multiple microcracks. Studies of bone crystal and collagen properties with several bone resorption inhibitors, including risedronate and raloxifene, showed no harmful effects. An increasing number (several hundreds) of mandibular osteonecrosis associated with bisphosphonate therapy has been reported. The typical patient was receiving injectable bisphosphonate therapy for bone cancer and had undergone dental work shortly before bisphosphonate administration. The mechanism of this adverse effect is poorly understood.
 

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