Osteoporosis: Devogelaer JP

Bergmann P, Body JJ, Boonen S, Boutsen Y, Devogelaer JP, Goemaere S, Kaufman JM, Reginster JY, Gangji V, Anonymous00023. · Laboratory of Clinical Chemistry, CHU Brugmann, Université Libre de Bruxelles, Bruxelles, Belgium. · Int J Clin Pract. · Pubmed #19125989 links to  free full text

Abstract: OBJECTIVES: To review the clinical value of bone turnover markers (BTM), to initiate and/or monitor anti-resorptive treatment for osteoporosis compared with bone mineral density (BMD) and to evaluate suitable BTM and changes in BTM levels for significance of treatment efficiency. METHODOLOGY: Consensus meeting generating guidelines for clinical practice after review and discussion of the randomised controlled trials or meta-analyses on the management of osteoporosis in postmenopausal women. RESULTS: Although the correlation between BMD and BTM is statistically significant, BTM cannot be used as predictive markers of BMD in an individual patient. Both are independent predictors of fracture risk, but BTM can only be used as an additional risk factor in the decision to treat. Current data do not support the use of BTM to select the optimal treatment. However, they can be used to monitor treatment efficiency before BMD changes can be evaluated. Early changes in BTM can be used to measure the clinical efficacy of an anti-resorptive treatment and to reinforce patient compliance. DISCUSSION: Determining a threshold of BTM reflecting an optimal long-term effect is not obvious. The objective should be the return to the premenopausal range and/or a decrease at least equal to the least significant change (30%). Preanalytical and analytical variability of BTM is an important limitation to their use. Serum C-terminal cross-linked telopeptide of type I collagen (CTX), procollagen 1 N terminal extension peptide and bone specific alkaline phosphatase (BSALP) appear to be the most suitable. Conclusion: Consensus regarding the use of BTM resulted in guidelines for clinical practice. BMD determines the indication to treat osteoporosis. BTM reflect treatment efficiency and can be used to motivate patients to persist with their medication.

Devogelaer JP, Goemaere S, Boonen S, Body JJ, Kaufman JM, Reginster JY, Rozenberg S, Boutsen Y. · Rheumatology Unit, Saint-Luc University Hospital, Université catholique de Louvain, Brussels, Belgium. · Osteoporos Int. · Pubmed #16217586 No free full text.

Abstract: Glucocorticoids (GCs) are frequently prescribed for various inflammatory and/or life-threatening conditions concerning many systems in the body. However, they can provoke many aftereffects, of which osteoporosis (OP) is one of the most crippling complications, with its host of fractures. The dramatic increase in bone fragility is mainly attributable to the GC-induced rapid bone loss in all skeletal compartments. We have reviewed the meta-analyses and randomized controlled studies reporting medical therapeutic interventions currently registered in Belgium for the management of GC-OP comparatively with a placebo. Based on this research, an expert meeting developed a consensus on the prevention and therapy of GC-OP. The pathophysiology of GC-OP is complex. Several factors, acting separately or synergistically, have been described. Their great number could help to understand the rapidity of bone loss and of bone fragility occurrence, indicating that a rapid therapeutic intervention should be implemented to avoid complications. All patients on GCs are threatened with OP, so the prevention and/or therapy of GC-OP should be considered not only for postmenopausal females, but also for osteopenic premenopausal females and for males put on a daily dose of at least 7.5 mg equivalent prednisolone that is expected to last at least 3 months. Non-pharmacological interventions, such as exercise and avoidance of tobacco and alcohol, should be recommended, even if their role is not definitely settled in GC-OP prevention. Supplemental calcium and vitamin D should be considered as the first-line therapy because of the decrease in intestinal calcium absorption provoked by GCs. They also could be considered either as isolated therapy in patients taking less than 7.5 mg prednisolone daily and/or for a predicted period shorter than 3 months or as adjuvant therapy to other more potent drugs. Hormone replacement therapy could be considered in young postmenopausal females on GC, such as in postmenopausal OP, or in men with low androgen levels. Calcitonin appears to have a protective effect on trabecular bone in GC-OP, just as in postmenopausal OP. There is an increasing body of evidence supporting the antifracture efficacy of bisphosphonates, notably alendronate and risedronate. Preventative and curative therapy of GC-OP should be maintained as long as the patient is on GC treatment and could be stopped after weaning from GC, because there is more than circumstantial evidence of some recovery of BMD when GCs are stopped. There is no indication in GC-OP for any combination of two antiresorptive agents (except for calcium and vitamin D) or for an antiresorptive and an anabolic agent. There is indeed no proof that the increased costs of combined treatments will translate into increased therapeutic efficacy.

Boonen S, Body JJ, Boutsen Y, Devogelaer JP, Goemaere S, Kaufman JM, Rozenberg S, Reginster JY. · Center for Metabolic Bone Diseases, Katholieke University Leuven, Leuven, Belgium. · Osteoporos Int. · Pubmed #15726235 No free full text.

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Body JJ, Bergmann P, Boonen S, Boutsen Y, Devogelaer JP, Goemaere S, Reginster JY, Rozenberg S, Kaufman JM. · Department of Medicine, CHU Brugmann and Institute J Bordet, Université Libre de Bruxelles, 4 place van Gehuchten, Brussels 1020, Belgium. · Osteoporos Int. · Pubmed #17690930 No free full text.

Abstract: Cancer treatment-induced bone loss (CTIBL) is one of the most important side effects of adjuvant antineoplastic treatment in hormone-dependent neoplasms. Chemotherapy, GnRH analogs and tamoxifen can induce marked bone loss in premenopausal women with early breast cancer. Aromatase inhibitors (AIs) are replacing tamoxifen as the preferred treatment for postmenopausal women. As a class effect, steroidal (exemestane) and non-steroidal (anastrozole and letrozole) AIs increase bone turnover and cause bone loss (4%-5% over 2 years). When compared to tamoxifen, the risk of getting a clinical fracture under AI treatment is increased by 35%-50%. In patients with prostate cancer, androgen deprivation therapy (ADT) increases bone turnover, reduces bone mass (4%-5% per year) and increases the fracture rate depending on the duration of therapy. Zoledronic acid can prevent accelerated bone loss induced by goserelin in premenopausal women, by letrozole in postmenopausal women and by ADT in men. More limited data indicate that weekly alendronate or risedronate could also be effective for preventing CTIBL. Initiation of therapy early, prior to the occurrence of severe osteoporosis, rather than after, may be more effective. Bisphosphonate treatment should be considered in osteoporotic but also in osteopenic patients if other risk factor(s) for fractures are present.

Devogelaer JP. · Department of Medicine, Arthritis Unit, Saint-Luc University Hospital, Université catholique de Louvain, 10, Avenue Hippocrate, UCL 5390, B-1200 Brussels, Belgium. · Rheum Dis Clin North Am. · Pubmed #17288975 No free full text.

Abstract: GCs constitute a therapeutic class largely used in clinical medicine for the curative or supportive treatment of various conditions involving the intervention of numerous medical specialties. Beyond their favorable therapeutic effects, GCs almost invariably provoke bone loss and a rapid increase in bone fragility, with its host of fractures. Men and postmenopausal women constitute a preferential target for the bone complications of GCs. The premenopausal status is not, however, a shelter; bone loss also happens in young women who are on GCs. Exposure to GCs yields a fracture risk exceeding the risk conferred by a low BMD per se. Therefore, some reason exists to settle the BMD threshold for therapeutic intervention not at -2.5 T-scores but at -1.0 or -1.5 T-scores, even if no prospective randomized trial so far endorses that opinion. Nowadays, bisphosphonate therapy should be proposed to every patient at risk for fragility fracture, along with calcium and vitamin D supplementation. Studies of other therapeutic modalities (eg, promoters of bone formation) are in progress.

Reginster JY, Devogelaer JP. · Department of Public Health, Epidemiology and Health Economics, University of Liège and the World Health Organization Collaborating Centre for Public Health Aspects of Bone Diseases, Liège, Belgium. · Clin Orthop Relat Res. · Pubmed #16462425 No free full text.

Abstract: Recently, selective estrogen receptor modulators have been developed for the management of osteoporosis based on antiosteoclastic properties similar to that of estrogens but with a safety profile including potential benefits on the breast, heart, and cognitive function. Raloxifene, the first selective estrogen receptor modulator to be marketed for the treatment of osteoporosis has shown reduction in spinal fracture risk in patients with low bone mineral density with (48%) or without (35%) prevalent vertebral fracture. Raloxifene also reduces nonvertebral fractures in high risk patients (47%). The decrease in Type I procollagen N-terminal propeptide at 1 year accounts for 28% of the total reduction in vertebral fracture risk. Raloxifene reduced the risk of estrogen receptor-positive invasive breast cancer by 84%. Among subjects with increased cardiovascular risk at baseline, those assigned to raloxifene had a 40% decrease in the risk of cardiovascular events compared with placebo. The definite anti-fracture efficacy of raloxifene at the spine, its plausible effect on non-spine fracture in high-risk patients and its beneficial effect on breast and heart make this compound an interesting approach for women presenting with osteoporosis. LEVEL OF EVIDENCE: Therapeutic study, level II (lesser quality randomized controlled trial [eg, < 80% followup, no blinding, or improper randomization]). See the Guidelines for Authors for a complete description of the levels of evidence.

Goffin E, Devogelaer JP. · Department of Nephrology, Université Catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium. · Transplant Proc. · Pubmed #16182824 No free full text.

Abstract: Three main bone disorders may occur after organ transplantation: epiphyseal impactions, avascular bone necrosis, and osteoporosis. Their main clinical characteristics, causes, diagnostic approaches, and therapies are discussed in this review.

Reginster JY, Devogelaer JP. · Centre Collaborateur de l'Institut Mondial de la Santé pour les Aspects de Santé Publique des Maladies Rhumatismales, Liège, Belgique. · Rev Med Liege. · Pubmed #15646737 No free full text.

Abstract: Major improvements have been observed, during the last ten years, in the management of postmenopausal osteoporosis. The most significant benefits have been obtained through the availability of new medications which have demonstrated their anti-fracture efficacy in the course of well conducted, scientifically sound studies. Due to the pharmacological properties of these new medications, treatment of osteoporosis can now be tailored to the needs of each and every single postmenopausal woman. Calcium supplementation (500 mg/day) should be offered to all post menopausal women unless dietary records show a sufficient intake. On the grounds of the high prevalence of low serum vitamin D levels in the ederly Belgian population, the systematic use of a calcium-vitamin D combination, after the age of 65 years, appears to be justified. Raloxifene is an interesting option for women with low mineral density or prevalent vertebral fractures. This molecule has demonstrated unequivocal anti-fracture efficacy at the level of the spine and is also caracterized by a beneficial effect on non-spinal fractures, in high risk women. Bisphosphonates (alendronate and risedronate) have shown the anti-fracture efficacy at the level of the axial and appendicular skeleton. The availability of a weekly formulation improves their compliance, notwithstanding the constrains related to the potential upper gastro-intestinal toxicity of these compounds. Bisphosphonates appear to be the first-line choice for patients with more severe osteoporosis and high risk to develop hip fractures. Teriparatide (1-34 Fragment of parathyroid hormone) is a new pharmacological option, oriented, mainly if not exclusively because of its parenteral administration and high cost, to patients with severe osteoporosis (low bone density and prevalent vertebral fracture(s). Strontium ranelate offers an anti-fracture efficacy at all skeleton sites and an oustanding overall tolerance and may play a main role in the future management of osteoporosis.

Devogelaer JP. · Rheumatology Unit, Saint-Luc University Hospital, Université catholique de Louvain, Brussels, Belgium. · Expert Opin Pharmacother. · Pubmed #15102576 No free full text.

Abstract: Osteoporosis is a frequent condition, which can lead to significant morbidity and even to increased mortality, owing to its complications (i.e., the fractures). Several therapies, mostly antiresorbing agents such as oestrogens, antioestrogens (chiefly raloxifene), calcitonin and bisphosphonates, are recognised for the treatment of the condition. More recently, parathyroid hormone has been added to the armamentarium of therapeutic agents. However, except for oestrogens, no other therapy alleviates climacteric symptoms. There is, therefore, some room for a therapeutic agent dealing with both osteoporosis and menopausal symptoms. Tibolone might be such an agent. However, so far, no fracture data are available; all existing studies have shown a positive action of tibolone on bone mineral density. No study has been tailored to study the antifracture efficacy. The Long Term Intervention on Fractures with Tibolone (LIFT) study has been started with the aim at filling the gap between bone mineral density maintenance and bone fracture prevention. At the same time, this study should help to understand the similarities and differences between tibolone and oestrogens as far as long-term bone action and safety are concerned, and should particularly help to clarify a possible link between tibolone use and breast cancer.

Devogelaer JP. · Rheumatology Unit, St-Luc University Hospital, Université catholique de Louvain, avenue Hippocrate 10, B-1200 Brussels, Belgium. · Eur J Endocrinol. · Pubmed #11517002 links to  free full text

This publication has no abstract.

Kaufman JM, Johnell O, Abadie E, Adami S, Audran M, Avouac B, Sedrine WB, Calvo G, Devogelaer JP, Fuchs V, Kreutz G, Nilsson P, Pols H, Ringe J, Van Haelst L, Reginster JY. · Unit for Osteoporosis and Metabolic Bone Diseases, Ghent University Hospital, Belgium. · Ann Rheum Dis. · Pubmed #11005775 links to  free full text

Abstract: Male osteoporosis represents an important, although long underestimated, public health problem. Both in men and in women aging is accompanied by continuous bone loss and by an exponential increase in the incidence of osteoporotic fracture, with a female to male incidence ratio of about 2 to 3 to 1 in the elderly for hip and vertebral fractures. Morbidity after osteoporotic fractures appears to be more serious and mortality more common in men than in women. To date, no single treatment has been proved to be effective and safe in published prospective studies. The present report, based on a systematic search of the literature on male osteoporosis, summarises the state of the art on the clinical consequences of male osteoporosis and its risk factors, in relation to the present state of knowledge about female osteoporosis. This constitutes the background for the design of rational clinical development strategies for therapeutic interventions in male osteoporosis. From this review of the literature it is apparent that notwithstanding the existing sex differences in pathophysiology of osteoporosis and the difference in age-specific incidence of osteoporotic fractures, there are also important similarities between osteoporosis in women and men. The higher incidence of fracture in women than in men results from quantitative differences in risk factors rather than from different risk factors. Even though there are sex differences in bone geometry, incidence of fracture seems to be similar in men and women for a same absolute areal bone mineral density. However, the lack of data on the changes in fracture rates in men resulting from pharmacological intervention, leading to changes in bone mineral density or bone turnover, remains the main limitation for extrapolation of established treatment outcomes from women to men.

Reginster JY, Bruyere O, Audran M, Avouac B, Body JJ, Bouvenot G, Brandi ML, Gennari C, Kaufman JM, Lemmel EM, Vanhaelst L, Weryha G, Devogelaer JP. · No affiliation provided · Calcif Tissue Int. · Pubmed #10954771 No free full text.

This publication has no abstract.

Devogelaer JP. · Department of Rheumatology, St-Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium. · Curr Opin Rheumatol. · Pubmed #10910187 No free full text.

Abstract: The main biologic action of bisphosphonates consists of the inhibition of osteoclastic bone resorption, and, at least, for the drugs introduced after etidronate, without any significant inhibition of bone mineralization. Bisphosphonates therefore play a major role in conditions that are characterized, at least partly, by an increased bone resorption. Primary and secondary osteoporosis by far constitute the most widespread indications for bisphosphonates, mostly because recent published trials have demonstrated their ability to prevent fractures. Potentially crippling conditions such as symptomatic Paget disease of bone remain a major therapeutic challenge for bisphosphonates, but the prevention of the major complications such as sarcoma has still to be proven. The availability of more potent bisphosphonates, less toxic for bones, has certainly widened the therapeutic interventions to asymptomatic patients, bearing in mind the various potential troublesome complications. Fibrous dysplasia resembles, in certain aspects, Paget disease; it is therefore not surprising that bisphosphonate therapy has been proposed in this indication. With the aging of world populations, more and more cancers will be diagnosed. For those with a bone metastatic propensity or malignant hematologic condition, such as multiple myeloma, the most recent generation of more potent bisphosphonates may bring more comfort to crippled patients and even, hopefully, have a direct antitumoral activity, if used synergistically with the armamentarium already available to the clinician. New indications for bisphosphonates include osteogenesis imperfecta both in children and adults. In the future, they might be used in the prevention of erosions in rheumatoid arthritis and of loosening of joint prostheses, as well as possibly in osteoarthritis. Now that the fear of theoretically freezing bone remodeling has been reasonably dismissed, potential uses for bisphosphonates might be considered nearly infinite.

Kaufman JM, Compston J, Audran MA, Avouac B, Devogelaer JP, Lemmel EM, Vanhaelst L, Reginster JY. · Universitair Ziekenhuis Gent, Ghent, Belgium. · Calcif Tissue Int. · Pubmed #10369725 No free full text.

This publication has no abstract.

Nzeusseu Toukap A, Depresseux G, Devogelaer JP, Houssiau FA. · Rheumatology Department, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Bruxelles, Belgium. · Lupus. · Pubmed #16130506 No free full text.

Abstract: Glucocorticoid (GC)-induced osteoporosis contributes to chronic damage in patients suffering from connective tissue diseases (CTD) such as systemic lupus erythematosus (SLE). In this study, performed in an highly selected cohort of premenopausal female CTD (mostly lupus) patients, given high-dose GC therapy for severe disease, we show that lumbar spine bone loss can be averted by treatment with oral disodium pamidronate combined with calcium salts and vitamin D3 supplements and not by calcium salts and vitamin D3 supplements alone. We stress the need for optimal GC-induced bone loss prevention therapy in premenopausal patients, a too often neglected issue in patients whose survival has dramatically improved over the last decades.

Reginster JY, Seeman E, De Vernejoul MC, Adami S, Compston J, Phenekos C, Devogelaer JP, Curiel MD, Sawicki A, Goemaere S, Sorensen OH, Felsenberg D, Meunier PJ. · Department of Epidemiology, Public Health and Health Economics, University of Liège, CHU Centre ville, 45 Quai Godefroid Kurth, 4020 Liège, Belgium. · J Clin Endocrinol Metab. · Pubmed #15728210 links to  free full text

Abstract: BACKGROUND: Strontium ranelate, a new oral drug shown to reduce vertebral fracture risk in postmenopausal women with osteoporosis, was studied in the Treatment of Peripheral Osteoporosis (TROPOS) study to assess its efficacy and safety in preventing nonvertebral fractures also. METHODS: Strontium ranelate (2 g/d) or placebo were randomly allocated to 5091 postmenopausal women with osteoporosis in a double-blind placebo-controlled 5-yr study with a main statistical analysis over 3 yr of treatment. FINDINGS: In the entire sample, relative risk (RR) was reduced by 16% for all nonvertebral fractures (P = 0.04), and by 19% for major fragility fractures (hip, wrist, pelvis and sacrum, ribs and sternum, clavicle, humerus) (P = 0.031) in strontium ranelate-treated patients in comparison with the placebo group. Among women at high risk of hip fracture (age > or = 74 yr and femoral neck bone mineral density T score < or = -3, corresponding to -2.4 according to NHANES reference) (n = 1977), the RR reduction for hip fracture was 36% (P = 0.046). RR of vertebral fractures was reduced by 39% (P < 0.001) in the 3640 patients with spinal x-rays and by 45% in the subgroup without prevalent vertebral fracture. Strontium ranelate increased bone mineral density throughout the study, reaching at 3 yr (P < 0.001): +8.2% (femoral neck) and +9.8% (total hip). Incidence of adverse events (AEs) was similar in both groups. CONCLUSION: This study shows that strontium ranelate significantly reduces the risk of all nonvertebral and in a high-risk subgroup, hip fractures over a 3-yr period, and is well tolerated. It confirms that strontium ranelate reduces vertebral fractures. Strontium ranelate offers a safe and effective means of reducing the risk of fracture associated with osteoporosis.

Tankó LB, Bagger YZ, Alexandersen P, Devogelaer JP, Reginster JY, Chick R, Olson M, Benmammar H, Mindeholm L, Azria M, Christiansen C. · Center for Clinical and Basic Research, Ballerup, Denmark. · J Bone Miner Res. · Pubmed #15312255 No free full text.

Abstract: Oral administration of calcitonin could improve compliance to long-term treatment. Efficacy and safety of a novel oral formulation was assessed on 277 postmenopausal women. The results show (1) effective enteral absorption, (2) marked inhibition of bone resorption with minimal alteration of formation, and (3) reproducibility of responses over 3 months. INTRODUCTION: We have recently introduced an Eligen technology-based oral formulation of salmon calcitonin (sCT) that effectively delivers the hormone to the circulation. The efficacy and safety during longer-term administration, however, has not been investigated in the target population. MATERIALS AND METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging clinical trial including 277 healthy postmenopausal women 55-85 years of age. Women received treatment with either daily (0.15, 0.4, 1.0, or 2.5 mg) or intermittent doses (1.0 mg, every other day) of sCT combined with the delivery agent (8-[N-2-hydroxi-5-chloro-benzoyl]-amino-caprylic acid, 200 mg) or placebo for 3 months. All participants received 1,000 mg calcium plus 400 IU vitamin D daily throughout the study. Efficacy parameters were the acute and/or pre-dose changes in serum and urinary C-terminal telopeptide of type I collagen (CTx), N-mid osteocalcin (OC), bone-specific alkaline phosphatase (BSALP), calcium, and parathyroid hormone (PTH) measured by established immunoassays. RESULTS: After the first dose, sCT evoked dose-dependent decreases in serum CTx (-60.8% to -81.8% from baseline) compared with placebo, reaching nadirs 2-3 h after drug intake, after which, gradual increases were observed. The simultaneous acute changes in OC were statistically nonsignificant. Area under the curve (AUC) of serum CTx responses at months 1 and 3 showed strong correlation with those at baseline (both r = 0.78, p < 0.001). At month 3, the placebo-corrected changes in the pre-dose value of serum and urinary CTx were significant only in the 1.0-mg dose group (-18.9% and -20.5%, respectively, p < 0.05). The placebo-corrected change in OC was -8.6 (p = 0.09), whereas the change in BSALP was -7.3 (p = 0.02). The oral formulation was well tolerated, with mild to moderate gastrointestinal and skin manifestations apparent mainly in the high-dose groups. CONCLUSION: The results of this 3-month trial show that the novel Eligen technology-based oral formulation of sCT has potential to become a safe and effective treatment for postmenopausal bone loss. Future trials are needed to assess the impact of long-term administration on changes in BMD and fracture risk.

Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey RD, Tonino RP, Rodriguez-Portales JA, Downs RW, Gupta J, Santora AC, Liberman UA, Anonymous00379. · Michigan Bone and Mineral Clinic, Detroit 48236, USA. · N Engl J Med. · Pubmed #15028823 links to  free full text

Abstract: BACKGROUND: Antiresorptive agents are widely used to treat osteoporosis. We report the results of a multinational randomized, double-blind study, in which postmenopausal women with osteoporosis were treated with alendronate for up to 10 years. METHODS: The initial three-year phase of the study compared three daily doses of alendronate with placebo. Women in the original placebo group received alendronate in years 4 and 5 and then were discharged. Women in the original active-treatment groups continued to receive alendronate during the initial extension (years 4 and 5). In two further extensions (years 6 and 7, and 8 through 10), women who had received 5 mg or 10 mg of alendronate daily continued on the same treatment. Women in the discontinuation group received 20 mg of alendronate daily for two years and 5 mg daily in years 3, 4, and 5, followed by five years of placebo. Randomized group assignments and blinding were maintained throughout the 10 years. We report results for the 247 women who participated in all four phases of the study. RESULTS: Treatment with 10 mg of alendronate daily for 10 years produced mean increases in bone mineral density of 13.7 percent at the lumbar spine (95 percent confidence interval, 12.0 to 15.5 percent), 10.3 percent at the trochanter (95 percent confidence interval, 8.1 to 12.4 percent), 5.4 percent at the femoral neck (95 percent confidence interval, 3.5 to 7.4 percent), and 6.7 percent at the total proximal femur (95 percent confidence interval, 4.4 to 9.1 percent) as compared with base-line values; smaller gains occurred in the group given 5 mg daily. The discontinuation of alendronate resulted in a gradual loss of effect, as measured by bone density and biochemical markers of bone remodeling. Safety data, including fractures and stature, did not suggest that prolonged treatment resulted in any loss of benefit. CONCLUSIONS: The therapeutic effects of alendronate were sustained, and the drug was well tolerated over a 10-year period. The discontinuation of alendronate resulted in the gradual loss of its effects.

Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U, Widmer A, Devogelaer JP, Kaufman JM, Jaeger P, Body JJ, Brandi ML, Broell J, Di Micco R, Genazzani AR, Felsenberg D, Happ J, Hooper MJ, Ittner J, Leb G, Mallmin H, Murray T, Ortolani S, Rubinacci A, Saaf M, Samsioe G, Verbruggen L, Meunier PJ. · Department of Medicine, University of Auckland, Auckland, New Zealand. · N Engl J Med. · Pubmed #11870242 links to  free full text

Abstract: BACKGROUND: Bisphosphonates are effective agents for the management of osteoporosis. Their low bioavailability and low potency necessitate frequent administration on an empty stomach, which may reduce compliance. Gastrointestinal intolerance limits maximal dosing. Although intermittent intravenous treatments have been used, the optimal doses and dosing interval have not been systematically explored. METHODS: We studied the effects of five regimens of zoledronic acid, the most potent bisphosphonate, on bone turnover and density in 351 postmenopausal women with low bone mineral density in a one-year, randomized, double-blind, placebo-controlled trial. Women received placebo or intravenous zoledronic acid in doses of 0.25 mg, 0.5 mg, or 1 mg at three-month intervals. In addition, one group received a total annual dose of 4 mg as a single dose, and another received two doses of 2 mg each, six months apart. Lumbar-spine bone mineral density was the primary end point. RESULTS: There were similar increases in bone mineral density in all the zoledronic acid groups to values for the spine that were 4.3 to 5.1 percent higher than those in the placebo group (P<0.001) and values for the femoral neck that were 3.1 to 3.5 percent higher than those in the placebo group (P<0.001). Biochemical markers of bone resorption were significantly suppressed throughout the study in all zoledronic acid groups. Myalgia and pyrexia occurred more commonly in the zoledronic acid groups, but treatment-related dropout rates were similar to that in the placebo group. CONCLUSIONS: Zoledronic acid infusions given at intervals of up to one year produce effects on bone turnover and bone density as great as those achieved with daily oral dosing with bisphosphonates with proven efficacy against fractures, suggesting that an annual infusion of zoledronic acid might be an effective treatment for postmenopausal osteoporosis.

Reid DM, Adami S, Devogelaer JP, Chines AA. · University of Aberdeen, Foresterhill, UK. · Calcif Tissue Int. · Pubmed #11730260 No free full text.

Abstract: Limited information is available on the effect of bisphosphonates in men receiving corticosteroid therapy. We studied 184 men among the patients enrolled in two, double-blind, placebo-controlled, 1-year studies with similar protocols. The studies evaluated the effects of risedronate in patients beginning corticosteroid treatment at a dose of at least 7.5 mg per day of prednisone or equivalent (prevention study) or continuing long-term treatment of corticosteroid at that dose (treatment study). The men received either placebo or risedronate (2.5 mg or 5 mg) daily, along with calcium supplementation (500-1000 mg). Endpoints included differences in bone mineral density (BMD) at the lumbar spine, femoral neck, and femoral trochanter, assessment of vertebral fractures, changes in biochemical markers of bone turnover, and overall safety. In the treatment study, risedronate 5 mg significantly (P < 0.01) increased lumbar spine BMD by 4.8% at the lumbar spine, 2.1% at the femoral neck, and 2.6% at the femoral trochanter compared with baseline values. In the prevention study, bone loss was prevented with risedronate 5 mg; in the placebo group, BMD decreased significantly (P < 0.01) by 3.4%, 3.3%, and 3.4% in the lumbar spine, femoral neck, and trochanter, respectively, at 1 year. The differences between risedronate 5 mg and placebo groups were significant at all skeletal sites in the prevention study (P < 0.01) and at the lumbar spine in the treatment study (P < 0.001). The 2.5 mg dose also had a positive effect on BMD, although of a lesser magnitude than the 5 mg dose. When the data from the two studies were combined, the incidence of vertebral fractures decreased 82.4% (95% confidence interval, 36.6%-95.1%) in the pooled risedronate groups compared with placebo (P = 0.008). Risedronate was well tolerated in men, with a similar incidence of upper gastrointestinal adverse events in the placebo and treatment groups. Daily treatment with risedronate increases bone density and decreases vertebral fracture risk within 1 year in men receiving corticosteroid therapy.

Goffin E, Devogelaer JP, Depresseux G, Squifflet JP, Pirson Y. · No affiliation provided · Lancet. · Pubmed #11386322 No free full text.

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Alexandersen P, Toussaint A, Christiansen C, Devogelaer JP, Roux C, Fechtenbaum J, Gennari C, Reginster JY, Anonymous00091. · Center for Clinical and Basic Research, Ballerup Byvej 222, 2750 Ballerup, Denmark. · JAMA. · Pubmed #11255425 links to  free full text

Abstract: CONTEXT: Data on the efficacy and safety of ipriflavone for prevention of postmenopausal bone loss are conflicting. OBJECTIVES: To investigate the effect of oral ipriflavone on prevention of postmenopausal bone loss and to assess the safety profile of long-term treatment with ipriflavone in postmenopausal osteoporotic women. DESIGN AND SETTING: Prospective, randomized, double-blind, placebo-controlled, 4-year study conducted in 4 centers in Belgium, Denmark, and Italy from August 1994 to July 1998. PARTICIPANTS: Four hundred seventy-four postmenopausal white women, aged 45 to 75 years, with bone mineral densities (BMDs) of less than 0.86 g/cm(2). INTERVENTIONS: Patients were randomly assigned to receive ipriflavone, 200 mg 3 times per day (n = 234), or placebo (n = 240); all received 500 mg/d of calcium. MAIN OUTCOME MEASURES: Efficacy measures included spine, hip, and forearm BMD and biochemical markers of bone resorption (urinary hydroxyproline corrected for creatinine and urinary CrossLaps [Osteometer Biotech, Herlev, Denmark] corrected for creatinine), assessed every 6 months. Laboratory safety measures and adverse events were recorded every 3 months. RESULTS: Based on intent-to-treat analysis, after 36 months of treatment, the annual percentage change from baseline in BMD of the lumbar spine for ipriflavone vs placebo (0.1% [95% confidence interval (CI), -7.9% to 8.1%] vs 0.8% [95% CI, -9.1% to 10.7%]; P =.14), or in any of the other sites measured, did not differ significantly between groups. The response in biochemical markers was also similar between groups (eg, for hydroxyproline corrected for creatinine, 20.13 mg/g [95% CI, 18.85-21.41 mg/g] vs 20.67 mg/g [95% CI, 19.41-21.92 mg/g]; P =.96); urinary CrossLaps corrected for creatinine, 268 mg/mol (95% CI, 249-288 mg/mol) vs 268 mg/mol (95% CI, 254-282 mg/mol); P =.81. The number of women with new vertebral fracture was identical or nearly so in the 2 groups at all time points. Lymphocyte concentrations decreased significantly (500/microL (0.5 x 10(9)/L]) in women treated with ipriflavone. Thirty-one women (13.2%) in the ipriflavone group developed subclinical lymphocytopenia, of whom 29 developed it during ipriflavone treatment. Of these, 15 (52%) of 29 had recovered spontaneously by 1 year and 22 (81%) of 29 by 2 years. CONCLUSIONS: Our data indicate that ipriflavone does not prevent bone loss or affect biochemical markers of bone metabolism. Additionally, ipriflavone induces lymphocytopenia in a significant number of women.

Boutsen Y, Jamart J, Esselinckx W, Devogelaer JP. · Department of Rheumatology, Université Catholique de Louvain, University Hospital in Mont-Godinne, Yvoir, Belgium. · J Bone Miner Res. · Pubmed #11149473 No free full text.

Abstract: The aim of this study was to compare the action of two regimens of intravenous (iv) pamidronate in the primary prevention of glucocorticoid-induced osteoporosis (GC-OP). The primary purpose of the study was to determine whether any differences in bone mineral density (BMD) appeared after 1 year. A secondary endpoint aimed at assessing the remodeling parameters in order to better understand the mechanisms of action of the various regimens. Thirty-two patients, who required first-time, long-term glucocorticoid therapy at a daily dose of at least 10 mg of prednisolone, were studied. Simultaneously with the initiation of their glucocorticoid treatment, patients also were randomly allocated to receive a single iv infusion of 90 mg of pamidronate at the start (group A); a first infusion of 90 mg of pamidronate followed, subsequently, by an iv infusion of 30 mg pamidronate every 3 months (group B); and a daily 800-mg elemental calcium supplement given as calcium carbonate (group C), which also was taken by patients in groups A and B. Patients were matched for starting glucocorticoid doses, sex, menopausal status, and hormonal replacement therapy. Lumbar spine and hip (total and subregions) BMDs were measured at the outset and repeated at 6-month intervals by dual-energy X-ray absorptiometry (DXA; Hologic QDR-2000). Bone turnover was assessed by measurement of total and bone-specific serum alkaline phosphatase activity (B-ALP), serum osteocalcin (OC), and serum C-telopeptide cross-links of type I collagen (CTX). After 1 year, the mean BMD changes for groups A, B, and C were, respectively, 1.7, 2.3, and -4.6% at the lumbar spine; 1.2, 1.2, and -3.1% at the femoral neck; 1.0, 2.6, and -2.2% for the total hip region. No difference was observed between pamidronate regimens but a highly significant difference was observed between both pamidronate regimens and the control group at the lumbar spine (p < 0.001), at the femoral neck (p < 0.01), and for the total hip (p < 0.05). A significant decrease of serum C-telopeptide was observed, after 3 months, in groups A and B (p = 0.029), but a sustained decrease of bone resorption over time was observed only in group B. As far as BMD evolution over 1 year was concerned, iv pamidronate, given either as a single infusion or once every 3 months, effectively achieved primary prevention of GC-OP.

Eastell R, Devogelaer JP, Peel NF, Chines AA, Bax DE, Sacco-Gibson N, Nagant de Deuxchaisnes C, Russell RG. · Department of Human Metabolism and Clinical Biochemistry, University of Sheffield, UK. · Osteoporos Int. · Pubmed #10928223 No free full text.

Abstract: The aim of the study was to assess risedronate's effect on bone mineral density in postmenopausal women with rheumatoid arthritis receiving glucocorticoids. We carried out a two center, 2 year, double-masked, placebo-controlled trial with a third year of nontreatment follow-up. We studied 120 women requiring long-term glucocorticoid therapy at > 2.5 mg/day prednisolone randomized to treatment with daily placebo; daily 2.5 mg risedronate; or cyclical 15 mg risedronate (2 out of 12 weeks). At 97 weeks, bone mineral density was maintained at the lumbar spine (+1.4%) and trochanter (+0.4%) in the daily 2.5 mg risedronate group, while significant bone loss occurred in the placebo group (-1.6%, p = 0.03; and 4.0%, p < 0.005, respectively). At the femoral neck, there was a nonsignificant bone loss in the daily 2.5 mg risedronate group (-1.0%) while in the placebo group bone mass decreased significantly (-3.6%, p < 0.001). The difference between placebo and daily 2.5 mg risedronate groups was significant at the lumbar spine (p = 0.009) and trochanter (p = 0.02) but did not reach statistical significance at the femoral neck. Although not significantly different from placebo at the lumbar spine, the overall effect of the cyclical regimen was similar to that of the daily 2.5 mg risedronate regimen. Treatment withdrawal led to bone loss in the risedronate groups that was significant at the lumbar spine. A similar number of patients experienced adverse events (including upper gastrointestinal events) across treatment groups and risedronate was generally well tolerated. Thus risedronate preserves bone mass in postmenopausal women with rheumatoid arthritis receiving glucocorticoids while patients receiving a placebo have significant bone loss.

Reid DM, Hughes RA, Laan RF, Sacco-Gibson NA, Wenderoth DH, Adami S, Eusebio RA, Devogelaer JP. · Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, United Kingdom. · J Bone Miner Res. · Pubmed #10841169 No free full text.

Abstract: Long-term use of high-dose corticosteroids often results in bone loss, which may lead to osteoporosis-related fractures. This was a multicenter, double-blind study in which 290 ambulatory men and women receiving high-dose oral corticosteroid therapy (prednisone > or = 7.5 mg/day or equivalent) for 6 or more months were randomized to receive placebo, risedronate 2.5 mg/day, or risedronate 5 mg/day for 12 months. All patients received calcium 1 g and vitamin D 400 IU daily. The primary endpoint was lumbar spine bone mineral density (BMD) at month 12. Additional measurements included BMD at the femoral neck and trochanter and the incidence of vertebral fractures. Overall, there were statistically significant treatment effects on BMD at 12 months at the lumbar spine (p < 0.001), femoral neck (p = 0.004), and trochanter (p = 0.010). Risedronate 5 mg increased BMD at 12 months by a mean (SEM) of 2.9% (0.49%) at the lumbar spine, 1.8% (0.46%) at the femoral neck, and 2.4% (0.54%) at the trochanter, whereas BMD was maintained only in the control group. Although not powered to show fracture efficacy, we observed a reduction in the incidence of vertebral fractures of 70% in the combined risedronate treatment groups, relative to placebo (p = 0.042). Risedronate was well tolerated, had a good safety profile, and was not associated with gastrointestinal adverse events. We conclude that risedronate increases BMD and potentially reduces the incidence of vertebral fractures in patients with corticosteroid-induced osteoporosis.