Osteoporosis: Body JJ

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.

This publication has no abstract.

Miller PD, Ward P, Pfister T, Leigh C, Body JJ. · Colorado Center for Bone Research, Lakewood, Colorado, USA. · Clin Exp Rheumatol. · Pubmed #19210886 No free full text.

Abstract: While intravenous (IV) bisphosphonates are well established in managing metastatic bone disease and hypercalcemia of malignancy, oral bisphosphonates are the primary treatment for postmenopausal osteoporosis. The availability of a well-tolerated, effective, IV bisphosphonate regimen for postmenopausal osteoporosis would increase physicians' options, allowing treatment of patients who cannot tolerate oral therapy, for whom oral bisphosphonates should be avoided or patients who are unable to comply with the oral dosing recommendations. Ibandronate is a potent, nitrogen-containing bisphosphonate, with proven efficacy and good tolerability when administered intermittently either orally or intravenously. Preclinical experience in animal models with IV ibandronate indicated that it had good renal tolerability. These data are supported by clinical pharmacology studies. Prolonged follow-up of patients receiving intermittent IV 15-30 second injections of 0.5-3 mg IV ibandronate has demonstrated no clinical evidence of renal toxicity in patients with postmenopausal osteoporosis. What is seen in controlled studies is not always the case in uncontrolled studies, however, no reports of renal failure have been received in post-marketing surveillance of >500,000 patients receiving IV ibandronate infusions in various indications including metastatic breast and prostate cancer. The good renal tolerability of IV ibandronate in patients with osteoporosis with glomerular filtration rates >30 mL/minute and without renal co-morbid conditions is reassuring.

Body JJ. · Service de Médecine, C.H.U. Brugmann, Bruxelles. · Rev Med Brux. · Pubmed #18949981 No free full text.

Abstract: The most frequent sites of osteoporotic fractures are the vertebrae, the hip, the forearm and the proximal humerus. Drugs that inhibit bone resorption constitute the mainstay for the treatment of postmenopausal osteoporosis. A recent meta-analysis indicates that vitamin D can reduce the risk of hip fractures only if calcium supplements are also administered. The effect of hormone replacement therapy on the risk of non vertebral fractures is less clear than on vertebral fractures. Raloxifene (a SERM) reduces the rate of vertebral fractures and of breast cancer, but it does not protect against hip fracture. Bisphosphonates are the most commonly used compounds to treat postmenopausal osteoporosis. The level of evidence for currently used bisphosphonates (alendronate, ibandronate, risedronate, zoledronate) to reduce vertebral fracture rate is maximal. Results of controlled clinical trials indicate a reduction in the risk of vertebral fractures of 40-50% and of 20-40% for non vertebral fractures, including hip fractures. However, their relative efficacy on hip fractures has been less well studied and remains more controversial. Long-term compliance of bisphosphonate therapy is improved by intermittent schemes. The most recent developpements concern the intravenous administration of ibandronate and even more of zoledronate (yearly infusions). The reduction in the rate of vertebral and hip fractures has been demonstrated in the main zoledronate trial and a prolongation of survival has been shown in the study including patients with a recent hip fracture. Whereas hyperparathyroidism is a cause of bone loss, the intermittent administration of parathyroid hormone or of its 1-34 fragment (teriparatide) exerts anabolic effects on the skeleton. The treatment is demanding and costly (daily sc injections during 18 months), requires some monitoring (serum and urinary calcium) but the results, at least for vertebral fractures, are quite favorable. Strontium ranelate is a less powerful stimulator of bone formation but it also reduces bone resorption. Its daily administration for 3 years reduces the risk of vertebral fractures and, to a lesser extent, of non vertebral fractures. Lastly, denosumab is a high affinity antibody against RANK Ligand that specifically blocks the formation and the activity of osteoclasts. The efficacy of this promising compound will soon be known.

Coleman RE, Body JJ, Gralow JR, Lipton A. · Academic Unit of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Sheffield, United Kingdom. · Cancer Treat Rev. · Pubmed #18486346 No free full text.

Abstract: Hormone-receptor-positive breast cancer in postmenopausal women is treated increasingly with aromatase inhibitors because of increased efficacy and reduced incidence of endometrial cancer compared with tamoxifen. However, aromatase inhibitor therapy increases bone turnover as a result of nearly complete oestrogen depletion, leading to increases in bone loss and fragility fractures that erode patients' functional independence and quality of life. Management of patients with aromatase inhibitor-associated bone loss (AIBL) is currently evolving and intervention strategies are under investigation. Although no treatments are specifically approved for AIBL, bisphosphonates are currently the intervention of choice for patients with low bone mineral density or evidence of rapid bone turnover, along with adequate calcium and vitamin D supplementation and a healthy lifestyle. In this setting, the majority of information available regarding bisphosphonate efficacy is from studies of intravenous zoledronic acid (4 mg) every 6 months. Data from four large international studies (three of identical design in postmenopausal women and one in premenopausal women) indicate that zoledronic acid is effective in the management of AIBL. Treatment algorithms based on risk factors and bone mineral density are under development, and the results of ongoing studies should help define optimal bone health management for patients undergoing aromatase inhibitor treatment for early breast cancer.

Ringe JD, Body JJ. · Medizinische Klinik IV, Klinikum Leverkusen, University of Cologne, Leverkusen, Germany. · Clin Exp Rheumatol. · Pubmed #18078631 No free full text.

Abstract: Several disorders of increased bone turnover and low bone mineral density (BMD) are associated with severe pain that is refractory to treatment with conventional and even opioid analgesics. Because of their ability to effectively improve the underlying pathogenesis of these disorders (i.e., reduce bone resorption and increase BMD), bisphosphonates are considered part of the palliative care of malignant bone-related pain and also appear to have some analgesic efficacy in other, non-malignant conditions. Ibandronate, a potent, nitrogen-containing bisphosphonate that can be given orally and intravenously, has demonstrated robust effects in relieving the pain associated with several malignant disorders. Unlike other available intravenous (i.v.) bisphosphonates, i.v. ibandronate is not associated with renal side effects, even at high doses such as 6 mg every 3 weeks. In addition, oral ibandronate (50 mg daily) is currently the only oral bisphosphonate proven to reduce and maintain bone pain scores below baseline for 2 years in patients with metastatic bone disease. Lower dose, less intense dosing regimens of ibandronate relieve bone pain in non-malignant conditions: i.v. ibandronate (2 mg every 3 months with or without an initial 4 mg injection) provides pain relief for patients with corticosteroid-induced osteoporosis, localised transient osteoporosis (bone marrow oedema) and sternocostoclavicular hyperostosis. Both oral and i.v. ibandronate are well tolerated. In conclusion, ibandronate offers an effective and convenient choice for the relief of bone pain in a wide variety of underlying bone conditions.

Aapro M, Abrahamsson PA, Body JJ, Coleman RE, Colomer R, Costa L, Crinò L, Dirix L, Gnant M, Gralow J, Hadji P, Hortobagyi GN, Jonat W, Lipton A, Monnier A, Paterson AH, Rizzoli R, Saad F, Thürlimann B. · Institut Multidisciplinaire d'Oncologie, Clinique de Genolier, Genolier, Switzerland. · Ann Oncol. · Pubmed #17906299 links to  free full text

Abstract: Bisphosphonates (BP) prevent, reduce, and delay cancer-related skeletal complications in patients, and have substantially decreased the prevalence of such events since their introduction. Today, a broad range of BP with differences in potency, efficacy, dosing, and administration as well as approved indications is available. In addition, results of clinical trials investigating the efficacy of BP in cancer treatment-induced bone loss (CTIBL) have been recently published. The purpose of this paper is to review the current evidence on the use of BP in solid tumours and provide clinical recommendations. An interdisciplinary expert panel of clinical oncologists and of specialists in metabolic bone diseases assessed the widespread evidence and information on the efficacy of BP in the metastatic and nonmetastatic setting, as well as ongoing research on the adjuvant use of BP. Based on available evidence, the panel recommends amino-bisphosphonates for patients with metastatic bone disease from breast cancer and zoledronic acid for patients with other solid tumours as primary disease. Dosing of BP should follow approved indications with adjustments if necessary. While i.v. administration is most often preferable, oral administration (clodronate, IBA) may be considered for breast cancer patients who cannot or do not need to attend regular hospital care. Early-stage cancer patients at risk of developing CTIBL should be considered for preventative BP treatment. The strongest evidence in this setting is now available for ZOL. Overall, BP are well-tolerated, and most common adverse events are influenza-like syndrome, arthralgia, and when used orally, gastrointestinal symptoms. The dose of BP may need to be adapted to renal function and initial creatinine clearance calculation is mandatory according to the panel for use of any BP. Subsequent monitoring is recommended for ZOL and PAM, as described by the regulatory authority guidelines. Patients scheduled to receive BP (mainly every 3-4 weeks i.v.) should have a dental examination and be advised on appropriate measures for reducing the risk of jaw osteonecrosis. BP are well established as supportive therapy to reduce the frequency and severity of skeletal complications in patients with bone metastases from different cancers.

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.

Bauss F, Body JJ. · Roche Diagnostics, Pharma Research Penzberg, Penzberg, Germany. · Anticancer Drugs. · Pubmed #15655407 No free full text.

Abstract: Bisphosphonates are widely used to prevent and treat skeletal complications of metastatic bone disease. There is increasing evidence that, besides inhibiting osteoclast activity and reducing bone resorption, bisphosphonates also have an anti-tumor effect. This paper reviews the preclinical data for ibandronate. Ibandronate increased the proportion of apoptotic tumor cells in vitro and in vivo, possibly following activation of caspase-like proteases. In vitro, ibandronate also prevented adhesion and spreading of tumor cells to bone, and tumor cell invasion. These inhibitory effects were additive when ibandronate was given with paclitaxel or docetaxel. In animal models of tumor-induced osteolysis, ibandronate significantly reduced the development of osteolytic lesions. Efficacy for the prevention and reduction of bone metastases was related to the timing of treatment; ibandronate treatment initiated prior to or shortly after tumor cell inoculation inhibited the growth of bone metastases and preserved skeletal integrity most effectively. As with other bisphosphonates, the influence of ibandronate on soft tissue metastases has been inconsistent. Overall, preclinical evidence supports the rationale for adjuvant treatment with ibandronate for patients at risk of metastatic bone disease. The renal safety profile of ibandronate supports its suitability for long-term adjuvant use, even with intermittent high dosing. Adjuvant clinical trials have been initiated. The ability of bisphosphonates to preserve skeletal integrity is also of benefit in other clinical settings. Recent studies in rat models demonstrate improved osseointegration of joint implants following ibandronate therapy, with potential application in patients with conditions such as degenerative arthritis or osteoporosis.

Body JJ. · Supportive Care Clinic, Clinic of Endocrinology and Bone Diseases and Laboratory of Endocrinology and Breast Cancer Research, Dept of Medicine, Institut J Bordet, 1 rue Héger-Bordet, Univ. Libre de Bruxelles, Brussels, Belgium. · Expert Opin Pharmacother. · Pubmed #12667119 No free full text.

Abstract: The two main therapeutic applications of bisphosphonates are tumour bone disease and osteoporosis. They constitute the standard treatment for cancer hypercalcaemia, and placebo-controlled trials have shown that the prolonged administration of bisphosphonates, such as pamidronate or clodronate, can reduce the frequency of complications from tumour bone disease due to metastatic breast cancer or myeloma by a quarter to one-half. The results obtained with the intravenous route appear to be more impressive and more rapidly obtained than with oral compounds. Both agents can reduce the risk of vertebral, wrist and hip fractures by 30 - 50%, whereas other antiresorptive agents, such as raloxifene (Eli Lilly & Co.) or calcitonin (Unigene Laboratories Inc.), have only been demonstrated to reduce the incidence of vertebral fractures. The short infusion time (4 mg over 15 min) offers a convenient therapy and constitutes the most evident advantage of zoledronic acid, which will improve patients' quality of life. Zoledronic acid has the potential to change the treatment of osteoporosis dramatically.

Body JJ. · Clinic of Endocrinology and Bone Diseases, and Supportive Care Clinic, Dept of Medicine, Institut J. Bordet, 1, rue Héger-Bordet Univ. Libre de Bruxelles, Brussels-Belgium. · Acta Clin Belg. · Pubmed #12534136 No free full text.

Abstract: Although there is a great need for better therapeutic approaches to the patient who presents with a fracture, osteoporotic fractures will remain a condition that is more amenable to prevention than treatment. Hormone replacement therapy (HRT) is still considered by many the mainstay for the prevention and the treatment of posrmenopausal osteoporosis. However, there are several controversies regarding HRT, especially the duration of treatment and the risks/benefits ratio. Recent studies have challenged the assumption that HRT conveys real long-term beneficial effects. Raloxifene or other "selective estrogen receptor modulators" (SERMs) should progressively replace HRT in elderly women. Bisphosphonates have demonstrated a clearcut efficacy in the treatment of osteoporosis. Alendronate and risedronate have been the most extensively studied bisphosphonates under randomized controlled trials conditions. Both agents can reduce the risk of vertebral and hip fractures by one-fourth to one-half. However, oral bisphosphonates are not without gastro-intestinal toxicity and strict adherence to constraining therapeutic schemes is mandatory. Intermittent treatments are already in use. Weekly alendronate is as efficient as daily therapy and improves treatment compliance. Newer more potent bisphosphonates, such as oral ibandronate or intravenous zoledronic acid, will allow much less frequent administration. The anti-fracture efficacy of yearly zoledronic acid infusions is thus currently tested. On the other hand, bone-forming agents, such as daily subcutaneous injections of teriparatide (rhPTH 1-34) offer exciting perspectives for the treatment of severe osteoporosis despite the complexity of such therapy.

Body JJ. · Supportive Care Clinic and Endocrinology/Bone Diseases Clinic, Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. · Bone. · Pubmed #12008163 No free full text.

Abstract: Calcitonin is a powerful inhibitor of osteoclast activity that exerts a rapid, transient, and reversible inhibition of bone resorption. Prolonged administration of parenteral calcitonin, by injections of 100 IU every 1 or 2 days, can prevent postmenopausal or postovariectomy bone loss, and is also able to increase trabecular bone mass among patients presenting an established osteoporosis. Prolonged treatment with calcitonin injections is, however, difficult to maintain over the long run. In addition to the ease of administration compared with the injectable forms, nasal calcitonin is much better tolerated, the side effects being rare and generally negligible. A prolonged administration of 200 IU intranasal calcitonin acutely inhibits parameters of bone resorption and can increase lumbar spine bone mineral density (BMD) by 1.7%-3.3% after 1 year. Lower doses also appear to be efficient to prevent early postmenopausal bone loss, but the data are conflictual. The results are more consistent in patients who already suffer from established osteoporosis. The increase in lumbar spine BMD is in the order of 1%-2% after 1 year with 200 IU daily. A therapeutic benefit of calcitonin at the level of the cortical bone has been less well demonstrated than for the trabecular bone. As for other antiosteoporotic therapies, the effect of calcitonin on the reduction of fracture risk has been examined less than the beneficial effect on trabecular bone mass. Currently, there is still no prospective, placebo-controlled study with a sufficient number of patients that demonstrates that long-term parenteral calcitonin administration reduces the risk of osteoporotic fractures. The efficacy of nasal calcitonin treatment to reduce vertebral fracture rate has been best examined in the PROOF (Prevent Recurrence of Osteoporotic Fractures) study. This was a prospective 5-year, placebo-controlled, dose-response study of nasal calcitonin (100, 200, or 400 IU daily). The increase in lumbar spine BMD was modest but significant and not clearly dose dependent, as was the reduction in bone turnover. The relative risk of developing new vertebral fractures was reduced by 33% at the end of the study in the 200-IU dose group (relative risk = 0.67, 95% CI 0.47-0.97, p = 0.03). There was also a nonsignificant reduction in the risk of hip fracture in this dose group. The doses of 100 and 400 IU of calcitonin also reduced the vertebral fracture risk, but the difference did not reach the classical level of statistical significance. A possible effect of calcitonin to enhance bone quality, which cannot be assessed by routinely available methods, is currently being investigated in a prospective placebo-controlled trial that could provide a rational explanation for these effects of calcitonin on the reduction in the vertebral fracture rate without much increase in bone mass or a marked reduction in bone turnover.

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.

Miller PD, Shergy WJ, Body JJ, Chen P, Rohe ME, Krege JH. · Colorado Center for Bone Research, Lakewood, 80227, USA. · J Rheumatol. · Pubmed #16078334 No free full text.

Abstract: OBJECTIVE: To compare the effects on back pain of teriparatide versus alendronate, we analyzed the reporting of back pain in a head to head comparator trial and a followup study. METHODS: In the comparator trial, women were randomized to receive either daily self-injected teriparatide 40 microg plus an oral placebo (n = 73), or daily oral alendronate 10 mg plus self-injected placebo (n = 73). Treatment was for a median 14 months. After completion of the comparator trial, 72% of these patients enrolled in a nontreatment followup study. Adverse events were recorded at each comparator trial visit and followup study visit, and the incidence of new or worsening back pain in each group was compared. RESULTS: During the comparator trial, compared with women randomized to alendronate 10 mg, women randomized to teriparatide 40 microg had reduced risk for any back pain (relative risk 0.27, 95% CI 0.09-0.82) and moderate or severe back pain (relative risk 0.19, 95% CI 0.04-0.86). The differences in the reporting of back pain between the teriparatide treated women and the alendronate treated women were sustained during an interval including the comparator trial plus 18 additional months. During an interval including the comparator trial plus 30 additional months, teriparatide treated patients had numerically fewer occurrences of back pain and moderate or severe back pain. CONCLUSION: Compared with women randomized to alendronate 10 mg, women randomized to teriparatide 40 microg had reduced risk of back pain during the trial and 2.5 years of followup.

Peretz A, Siderova V, Body JJ, Dumon JC, Rozenberg S, Fellemans C, Fuss M, Bergmann P, Anonymous00115. · The Internal Medicine Department, CHU Brugmann, 4 place Van Gehuchten, B-1020, Brussels, Belgium. · Maturitas. · Pubmed #12590006 No free full text.

Abstract: INTRODUCTION: Different bisphosphonates have been shown to increase bone mineral density (BMD) and reduce the risk of fracture in osteoporotic patients. It is unclear how shifting from a treatment with one bisphosphonate to another will influence the evolution of BMD and bone turnover. METHODS: In the present study, we followed BMD (DXA, Hologic QDR1000) of the lumbar spine (BMDL) and of the total hip (BMDH), bone alkaline phosphatase (Ostase, Hibritech), and urinary collagen cross links (pyridinoline, deoxypyridinoline, Biorad) in 39 patients treated with IV pamidronate (60 mg/3 months) since at least 2 years and who were shifted to oral alendronate (10 mg/day, n=18) or left to IV pamidronate (n=21) for 2 more years. RESULTS: BMD increased similarly and significantly in both groups after 2 additional years of treatment as compared to baseline (P<0.05, sign test). BMDL: +3.8% in the alendronate group vs +4.1% in the pamidronate group; BMDH: +4.3% in alendronate group vs +3.6% in pamidronate group, There was no significant change in the biological parameters of bone turnover in any group. CONCLUSION: The increase of BMD with both bisphosphonates in these previously treated patients was as expected after a 2 more years of treatment. Alendronate administration did not induce a larger gain in BMD as compared to cyclic pamidronate. Bone turnover was no longer affected by switching the bisphosphonate treatment.

Body JJ, Gaich GA, Scheele WH, Kulkarni PM, Miller PD, Peretz A, Dore RK, Correa-Rotter R, Papaioannou A, Cumming DC, Hodsman AB. · Department of Medicine, Institut J. Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium. · J Clin Endocrinol Metab. · Pubmed #12364430 links to  free full text

Abstract: Teriparatide (rDNA origin) injection [recombinant human PTH (1-34)] stimulates bone formation, increases bone mineral density (BMD), and restores bone architecture and integrity. In contrast, bisphosphonates reduce bone resorption and increase BMD. We compared the effects of teriparatide and alendronate sodium on BMD, nonvertebral fracture incidence, and bone turnover in 146 postmenopausal women with osteoporosis. Women were randomized to either once-daily sc injections of teriparatide 40 micro g plus oral placebo (n = 73) or oral alendronate 10 mg plus placebo injection (n = 73). Median duration of treatment was 14 months. At 3 months, teriparatide increased lumbar spine BMD significantly more than did alendronate (P < 0.001). Lumbar spine-BMD increased by 12.2% in the teriparatide group and 5.6% in the alendronate group (P < 0.001 teriparatide vs. alendronate). Teriparatide increased femoral neck BMD and total body bone mineral significantly more than did alendronate, but BMD at the one third distal radius decreased, compared with alendronate (P < or = 0.05). Nonvertebral fracture incidence was significantly lower in the teriparatide group than in the alendronate group (P < 0.05). Both treatments were well tolerated despite transient mild asymptomatic hypercalcemia with teriparatide treatment. In conclusion, teriparatide, a bone formation agent, increased BMD at most sites and decreased nonvertebral fractures more than alendronate.

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.

Rizzoli R, Thiébaud D, Bundred N, Pecherstorfer M, Herrmann Z, Huss HJ, Rückert F, Manegold C, Tubiana-Hulin M, Steinhauer EU, Degardin M, Thürlimann B, Clemens MR, Eghbali H, Body JJ. · World Health Organization Collaborating Center for Osteoporosis and Bone Diseases, Department of Internal Medicine, University Hospital, Geneva, Switzerland. · J Clin Endocrinol Metab. · Pubmed #10522993 links to  free full text

Abstract: The pathogenesis of hypercalcemia of malignancy comprises increased net bone resorption and enhanced renal tubular reabsorption of calcium (Ca). To evaluate the prevalence of an increased renal tubular reabsorption of Ca index [tubular reabsorption of calcium index (TRCaI)] in cancer patients with hypercalcemia and of elevated circulating levels of PTH-related protein (PTHrP), which is recognized as a major mediator of this syndrome, we investigated 315 well rehydrated patients, aged 58.1 +/- 0.7 yr (mean +/- SEM), with hypercalcemia [albumin-corrected plasma Ca (pCa), >2.7 mmol/L] secondary to histologically proven malignancy. Changes in pCa and, therefore, various Ca filtered loads were obtained by different degrees of bone resorption inhibition achieved with a single infusion of the bisphosphonate ibandronate, given at various doses on a randomized, double blind basis. PTHrP was determined at baseline in 147 of the patients and 7 days after bisphosphonate therapy in 73. Before ibandronate therapy, pCa was 3.36 +/- 0.02 mmol/L, mean TRCaI was increased at 3.09 +/- 0.03 mmol/L glomerular filtration rate (GFR; normal, 2.40-2.90), and 65% of patients had TRCaI above 2.90 mmol/L GFR. Mean serum PTHrP levels were 4.9 +/- 0.5 pmol/L (normal, <2.5) and values above the normal range were found in 53% of the patients (76% in lung and upper respiratory tract malignancies). By 7 days after the infusion of ibandronate, a decrease in pCa of 0.69 +/- 0.03 mmol/L (20.0 +/- 0.7%; P < 0.001) and in bone resorption [mean change in fasting urinary Ca, 0.09 +/- 0.04 mmol/L GFR (47.6 +/- 8.6%; P < 0.001) and 14.4 +/- 1.7 nmol/mmol (27.6 +/- 10.6%; P < 0.01) in deoxypyridinoline] was observed. TRCaI was slightly lowered by 0.30 +/- 0.09 mmol/L GFR. Mean changes in PTHrP, 1,25-dihydroxyvitamin D3, and PTH were +0.7 +/- 0.4 (P = NS), +27.6 +/- 3.0 (P < 0.001), and +2.9 +/- 0.8 (P < 0.005) pmol/L, respectively. After ibandronate treatment, the relative risk of relapsing hypercalcemia was particularly increased (3.43-fold) in lung and upper respiratory tract malignancies. These results obtained in a large cohort of patients indicate a significant prevalence of an increased renal tubular reabsorption of calcium index in hypercalcemia of malignancy and a substantial proportion of patients with detectable PTHrP.

Body JJ, Moreau M, Bergmann P, Paesmans M, Dekelver C, Lemaire ML. · Service de Médecine Interne, C.H.U. Brugmann, Bruxelles. · Rev Med Brux. · Pubmed #18949979 No free full text.

Abstract: Osteoporosis is a major public health problem. For the time being, the diagnosis of osteoporosis relies on densitometry (T-score < -2.5 by DXA), although the risk of fracture depends also on other factors than the bone mass. Osteoporosis diagnosis (DXA) must be distinguished from the individual risk assessment of fracture. Different risk factors complementary to bone mass have been already validated in different populations. These include an old age, a history of fracture after the age of 50, a familial history of hip fracture (father or mother), a low BMI (< 20), corticoid treatment (> 3 months), tabagism and excessive alcohol consumption. A WHO taskforce has combined these different factors in order to integrate them in a 10-years predictive risk model of fracture (FRAX**). This model should still be validated in different populations, especially in populations not included in its development, which is the case for Belgium. We are evaluating these different risk factors for fracture in a Brussels population of 5000 women (60-80 years) who will be followed each year during 10 years. We also assess the predictive value of other risk factors for fracture not included in the WHO model (tendency to fall, use of sleeping pills, early non substituted menopause, sedentarity, ...). In an interim analysis of the first 452 women included and with data yet available at the time of this writing, we could find a significant (P < 0.05) relationship between diagnosis of osteoporosis at DXA and the number of risk factors, age > 70 years, a personal history of fracture after 50 years and a BMI < 20.

Hadji P, Body JJ, Aapro MS, Brufsky A, Coleman RE, Guise T, Lipton A, Tubiana-Hulin M. · Department of Gynecology, Philipps-University of Marburg, Marburg, Germany. · Ann Oncol. · Pubmed #18448451 links to  free full text

Abstract: BACKGROUND: Recent studies indicate that women with breast cancer are at increased risk of fracture compared with their age-matched peers. Current treatment guidelines are inadequate for averting fractures in osteopenic women, especially those receiving aromatase inhibitor (AI) therapy. Therefore, we sought to identify clinically relevant risk factors for fracture that can be used to assess overall fracture risk and to provide practical guidance for preventing and treating bone loss in women with breast cancer receiving AI therapy. METHODS: Systematic review of pertinent information from published literature and meeting abstracts through December 2007 was carried out to identify factors contributing to fracture risk in women with breast cancer. An evidence-based medicine approach was used to select risk factors that can be used to determine when to initiate bisphosphonate treatment of aromatase inhibitor-associated bone loss (AIBL). RESULTS: Fracture risk factors were chosen from large, well-designed, controlled, population-based trials in postmenopausal women. Evidence from multiple prospective clinical trials in women with breast cancer was used to validate AI therapy as a fracture risk factor. Overall, eight fracture risk factors were validated in women with breast cancer: AI therapy, T-score <-1.5, age >65 years, low body mass index (BMI <20 kg/m(2)), family history of hip fracture, personal history of fragility fracture after age 50, oral corticosteroid use >6 months, and smoking. Treatment recommendations were derived from randomized clinical trials. CONCLUSIONS: The authors recommend the following for preventing and treating AIBL in women with breast cancer. All patients initiating AI therapy should receive calcium and vitamin D supplements. Any patient initiating or receiving AI therapy with a T-score >/=-2.0 and no additional risk factors should be monitored every 1-2 years for change in risk status and bone mineral density (BMD). Any patient initiating or receiving AI therapy with a T-score <-2.0 should receive bisphosphonate therapy. Any patient initiating or receiving AI therapy with any two of the following risk factors-T-score <-1.5, age >65 years, low BMI (<20 kg/m(2)), family history of hip fracture, personal history of fragility fracture after age 50, oral corticosteroid use >6 months, and smoking-should receive bisphosphonate therapy. BMD should be monitored every 2 years, and treatment should continue for at least 2 years and possibly for as long as AI therapy is continued. To date, the overwhelming majority of clinical evidence supports zoledronic acid 4 mg every 6 months to prevent bone loss in women at high risk. Although there is a trend towards fewer fractures with zoledronic acid, studies completed to date have not been designed to capture significant differences in fracture rate, and longer follow-up is needed.

Devogelaer JP, Brown JP, Burckhardt P, Meunier PJ, Goemaere S, Lippuner K, Body JJ, Samsioe G, Felsenberg D, Fashola T, Sanna L, Ortmann CE, Trechsel U, Krasnow J, Eriksen EF, Garnero P. · Saint-Luc University Hospital, Université catholique de Louvain, Bruxelles, Belgium. · Osteoporos Int. · Pubmed #17516022 No free full text.

Abstract: SUMMARY: In a 5-year study involving 119 postmenopausal women, zoledronic acid 4 mg given once-yearly for 2, 3 or 5 years was well tolerated with no evidence of excessive bone turnover reduction or any safety signals. BMD increased significantly. Bone turnover markers decreased from baseline and were maintained within premenopausal reference ranges. INTRODUCTION: After completion of the core study, two consecutive, 2-year, open-label extensions investigated the efficacy and safety of zoledronic acid 4 mg over 5 years in postmenopausal osteoporosis. METHODS: In the core study, patients received 1 to 4 mg zoledronic acid or placebo. In the first extension, most patients received 4 mg per year and then patients entered the second extension and received 4 mg per year or calcium only. Patients were divided into three subgroups according to years of active treatment received (2, 3 or 5 years). Changes in BMD and bone turnover markers (bone ALP and CTX-I) were assessed. RESULTS: All subgroups showed substantial increases in BMD and decreases in bone markers. By the end of the core study, 37.5% of patients revealed a suboptimal reduction (< 30%) of bone ALP levels. After subsequent study drug administration during the extensions, there was no evidence of progressive reduction of bone turnover markers. Furthermore, increased marker levels after treatment discontinuation demonstrates preservation of bone remodelling capacity. CONCLUSIONS: This study showed that zoledronic acid 4 mg once-yearly was well tolerated and effective in reducing biomarkers over 5 years. Detailed analysis of bone marker changes, however, suggests that this drug regimen causes insufficient reduction of remodelling activity in one third of patients.

Kaufman JM, Body JJ, Boonen S, Devogelaer JP, Raeman F, Rozenberg S, Reginster JY. · Universiteit Gent, Belgium. · Rev Med Liege. · Pubmed #10941311 No free full text.

Abstract: Osteoporosis is now considered as a major public health issue and a serious threat for the quality of life of elderly women. Several new compounds are currently marketed for the prevention and treatment of involutional osteoporosis in women. Therefore, it is important to offer to the practitioners pragmatic solutions to be used for the rational management of this disorder. This article is the result of a national consensus offering practical guidelines for the management of osteoporotic patients, based on the current published data.

Body JJ, Sternon J. · Clinique des Soins Supportifs, Institut J. Bordet, U.L.B. · Rev Med Brux. · Pubmed #10748686 No free full text.

Abstract: The prevention of osteoporotic fractures in post-menopausal women must be viewed in the framework of the treatment of menopause. SERMs ("Selective Estrogen Receptor Modulators") derivative from steroid hormones have estrogenic and antiestrogenic properties according to the substance and the target tissue. Raloxifene is a second generation SERM. It increases bone mass by 1 to 3% according to the measured site and, after 3 years of therapy at the dose of 60 mg per day, it reduces the incidence of vertebral fractures by 30 to 50% if patients have or do not have vertebral fractures before therapy. This drug is approved for the prevention of vertebral fractures in post-menopausal women at increased risk of fractures. A significant reduction in the incidence of hip fractures has not been demonstrated. Raloxifene exerts favorable effects on cardiovascular risk factors but one has to wait for the results of controlled prospective trials before concluding that raloxifene reduces the risk of atherogeniec disease. Preliminary results indicate a substantial reduction of the risk of invasive breast cancer, still to be confirmed. The incidence of vaginal bleeding does not differ from placebo as raloxifene does not stimulate endometrial proliferation. The most serious adverse event, although infrequent, consists in an increase of the relative risk of thromboembolic disease by 3.1 as compared to placebo. Longer term studies are necessary to compare raloxifene with the estrogen replacement therapy and to determine the extra-bone effects.