The role of biochemical of bone turnover markers in osteoporosis and metabolic bone disease: a consensus paper of the Belgian Bone Club.

The exact role of biochemical markers of bone turnover in the management of metabolic bone diseases remains a topic of controversy. In this consensus paper, the Belgian Bone Club aimed to provide a state of the art on the use of these biomarkers in different clinical or physiological situations like in postmenopausal women, osteoporosis in men, in elderly patients, in patients suffering from bone metastasis, in patients with chronic renal failure, in pregnant or lactating women, in intensive care patients, and in diabetics. We also gave our considerations on the analytical issues linked to the use of these biomarkers, on potential new emerging biomarkers, and on the use of bone turnover biomarkers in the follow-up of patients treated with new drugs for osteoporosis.

Recommendations for an update of the 2010 European regulatory guideline on clinical investigation of medicinal products used in the treatment of osteoarthritis and reflections about related clinically relevant outcomes: expert consensus statement.

OBJECTIVE: The European Society on Clinical and Economic aspects of Osteoporosis and Osteoarthritis (ESCEO) organised a working group to evaluate the need for updating the current European guideline on clinical investigation of drugs used in the treatment of osteoarthritis (OA). DESIGN: Areas of potential attention were identified and the need for modifications, update or clarification was examined. Proposals were then developed based on literature reviews and through a consensus process. RESULTS: It was agreed that the current guideline overall still reflects the current knowledge in OA, although two possible modifications were identified. The first relates to the number and timing of measurements required as primary endpoints during clinical trials of symptom-relieving drugs, either drugs with rapid onset of action or slow acting drugs. The suggested modifications are intended to take into consideration the time related clinical need and expected time response to these drugs - i.e., a more early effect for the first category in addition to the maintenance of effect, a more continuous benefit over the long-term for the latter - in the timing of assessments. Secondly, values above which a benefit over placebo should be considered clinically relevant were considered. Based on literature reviews, the most consensual values were determined for primary endpoints of both symptom-relieving drugs (i.e., pain intensity on a visual analogue scale (VAS)) and disease-modifying drugs (i.e., radiographic joint-space narrowing). CONCLUSIONS: This working document might be considered by the European regulatory authorities in a future update of the guideline for the registration of drugs in OA.

Goal-directed treatment of osteoporosis in Europe.

UNLABELLED: Despite the proven predictive ability of bone mineral density, Fracture Risk Assessment Tool (FRAX®), bone turnover markers, and fracture for osteoporotic fracture, their use as targets for treatment of osteoporosis is limited. INTRODUCTION: Treat-to-target is a strategy applied in several fields of medicine and has recently become an area of interest in the management of osteoporosis. Its role in this setting remains controversial. This article was prepared following a European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) working group meeting convened under the auspices of the International Osteoporosis Foundation (IOF) to discuss the feasibility of applying such a strategy in osteoporosis in Europe. METHODS: Potential targets range from the absence of an incident fracture to fixed levels of bone mineral density (BMD), a desired FRAX® score, a specified level of bone turnover markers or indeed changes in any one or a combination of these parameters. RESULTS: Despite the proven predictive ability of all of these variables for fracture (particularly BMD and FRAX), their use as targets remains limited due to low sensitivity, the influence of confounders and current lack of evidence that targets can be consistently reached. CONCLUSION: ESCEO considers that it is not currently feasible to apply a treat-to-target strategy in osteoporosis, though it did identify a need to continue to improve the targeting of treatment to those at higher risk (target-to-treat strategy) and a number of issues for the research agenda. These include international consensus on intervention thresholds and definition of treatment failure, further exploration of the relationship between fracture and BMD, and FRAX and treatment efficacy and investigation of the potential of short-term targets to improve adherence.

Treatment of osteoporosis in men.

SUMMARY: Aspects of osteoporosis in men, such as screening and identification strategies, definitions of diagnosis and intervention thresholds, and treatment options (both approved and in the pipeline) are discussed. INTRODUCTION: Awareness of osteoporosis in men is improving, although it remains under-diagnosed and under-treated. A European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) workshop was convened to discuss osteoporosis in men and to provide a report by a panel of experts (the authors). METHODS: A debate with an expert panel on preselected topics was conducted. RESULTS AND CONCLUSIONS: Although additional fracture data are needed to endorse the clinical care of osteoporosis in men, consensus views were reached on diagnostic criteria and intervention thresholds. Empirical data in men display similarities with data acquired in women, despite pathophysiological differences, which may not be clinically relevant. Men should receive treatment at a similar 10-year fracture probability as in women. The design of mixed studies may reduce the lag between comparable treatments for osteoporosis in women becoming available in men.

Management of glucocorticoid-induced osteoporosis.

This review summarizes the available evidence-based data that form the basis for therapeutic intervention and covers the current status of glucocorticoid-induced osteoporosis (GIOP) management, regulatory requirements, and risk-assessment options. Glucocorticoids are known to cause bone loss and fractures, yet many patients receiving or initiating glucocorticoid therapy are not appropriately evaluated and treated. An European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis workshop was convened to discuss GIOP management and to provide a report by a panel of experts. An expert panel reviewed the available studies that discussed approved therapeutic agents, focusing on randomized and controlled clinical trials reporting on bone mineral density and/or fracture risk of at least 48 weeks' duration. There is no evidence that GIOP and postmenopausal osteoporosis respond differently to treatments. The FRAX algorithm can be adjusted according to glucocorticoid dose. Available antiosteoporotic therapies such as bisphosphonates and teriparatide are efficacious in GIOP management. Several other agents approved for the treatment of postmenopausal osteoporosis may become available for GIOP. It is advised to stop antiosteoporotic treatment after glucocorticoid cessation, unless the patient remains at increased risk of fracture. Calcium and vitamin D supplementation as an osteoporosis-prevention measure is less effective than specific antiosteoporotic treatment. Fracture end-point studies and additional studies investigating specific subpopulations (pediatric, premenopausal, or elderly patients) would strengthen the evidence base and facilitate the development of intervention thresholds and treatment guidelines.

Extraskeletal benefits and risks of calcium, vitamin D and anti-osteoporosis medications.

UNLABELLED: Drugs used for the prevention and the treatment of osteoporosis exert various favourable and unfavourable extra-skeletal effects whose importance is increasingly recognized notably for treatment selection. INTRODUCTION: The therapeutic armamentarium for the prevention and the treatment of osteoporosis is increasingly large, and possible extra-skeletal effects of available drugs could influence the choice of a particular compound. METHODS: The present document is the result of a national consensus, based on a systematic and critical review of the literature. RESULTS: Observational research has suggested an inverse relationship between calcium intake and cardiovascular diseases, notably through an effect on blood pressure, but recent data suggest a possible deleterious effect of calcium supplements on cardiovascular risk. Many diverse studies have implicated vitamin D in the pathogenesis of clinically important non-skeletal functions or diseases, especially muscle function, cardiovascular disease, autoimmune diseases and common cancers. The possible effects of oral or intravenous bisphosphonates are well-known. They have been associated with an increased risk of oesophageal cancer or atrial fibrillation, but large-scale studies have not found any association with bisphosphonate use. Selective oestrogen receptor modulators have demonstrated favourable or unfavourable extra-skeletal effects that vary between compounds. Strontium ranelate has a limited number of non-skeletal effects. A reported increase in the risk of venous thromboembolism is not found in observational studies, and very rare cases of cutaneous hypersensitivity reactions have been reported. Denosumab has been introduced recently, and its extra-skeletal effects still have to be assessed. CONCLUSION: Several non-skeletal effects of bone drugs are well demonstrated and influence treatment choices.

Maintenance of antifracture efficacy over 10 years with strontium ranelate in postmenopausal osteoporosis.

UNLABELLED: In an open-label extension study, BMD increased continuously with strontium ranelate over 10 years in osteoporotic women (P < 0.01). Vertebral and nonvertebral fracture incidence was lower between 5 and 10 years than in a matched placebo group over 5 years (P < 0.05). Strontium ranelate's antifracture efficacy appears to be maintained long term. INTRODUCTION: Strontium ranelate has proven efficacy against vertebral and nonvertebral fractures, including hip, over 5 years in postmenopausal osteoporosis. We explored long-term efficacy and safety of strontium ranelate over 10 years. METHODS: Postmenopausal osteoporotic women participating in the double-blind, placebo-controlled phase 3 studies SOTI and TROPOS to 5 years were invited to enter a 5-year open-label extension, during which they received strontium ranelate 2 g/day (n = 237, 10-year population). Bone mineral density (BMD) and fracture incidence were recorded, and FRAX® scores were calculated. The effect of strontium ranelate on fracture incidence was evaluated by comparison with a FRAX®-matched placebo group identified in the TROPOS placebo arm. RESULTS: The patients in the 10-year population had baseline characteristics comparable to those of the total SOTI/TROPOS population. Over 10 years, lumbar BMD increased continuously and significantly (P < 0.01 versus previous year) with 34.5 ± 20.2% relative change from baseline to 10 years. The incidence of vertebral and nonvertebral fracture with strontium ranelate in the 10-year population in years 6 to 10 was comparable to the incidence between years 0 and 5, but was significantly lower than the incidence observed in the FRAX®-matched placebo group over 5 years (P < 0.05); relative risk reductions for vertebral and nonvertebral fractures were 35% and 38%, respectively. Strontium ranelate was safe and well tolerated over 10 years. CONCLUSIONS: Long-term treatment with strontium ranelate is associated with sustained increases in BMD over 10 years, with a good safety profile. Our results also support the maintenance of antifracture efficacy over 10 years with strontium ranelate.

Post hoc analysis of a single IV infusion of zoledronic acid versus daily oral risedronate on lumbar spine bone mineral density in different subgroups with glucocorticoid-induced osteoporosis.

This study summarizes the treatment effect of zoledronic acid infusion on lumbar spine bone mineral density in different subgroups with glucocorticoid-induced osteoporosis. Zoledronic acid is significantly more effective than risedronate in increasing lumbar spine (LS) bone mineral density (BMD) in both prevention and treatment of glucocorticoid-induced osteoporosis. Introduction In patients on glucocorticoids, a single zoledronic acid infusion significantly increased BMD versus daily oral risedronate. We assessed treatment effect on LS BMD in different patient subgroups at month 12 that contributed to the risk of osteoporosis in addition to glucocorticoids. Methods Patients randomized to a single IV infusion of zoledronic acid 5 mg or risedronate (5 mg/day) and stratified based on glucocorticoids duration [treatment (>3 months) and prevention (≤ 3 months) subpopulations]were subgrouped by age; gender; menopausal status in women; dose and duration of prednisone during the trial; and baseline serum 25-OH vitamin D, LS BMD T-score, creatinine clearance, and concomitant medication use. Results At month 12, zoledronic acid significantly increased LS BMD versus risedronate in patients ≤ 74 years (P<0.05) in the treatment and 65-74 years (P = 0.0008) in the prevention subpopulation. At month 12, zoledronic acid significantly increased LS BMD versus risedronate in both subpopulations irrespective of gender (all P<0.05), cumulative prednisone dose (all P<0.01), and postmenopausal status (all P<0.05). In premenopausal women, in both subpopulations, zoledronic acid significantly increased total hip BMD (all P<0.05) versus risedronate at month 12 but not LS BMD. Osteoporotic patients in the prevention (P=0.0189) and osteopenic patients in the treatment subpopulation (P=0.0305) showed significant LS BMD increases with zoledronic acid versus risedronate at month 12. Conclusions This post hoc analysis suggests that zoledronic acid is significantly more effective than risedronate in increasing LS BMD in prevention and treatment of glucocorticoid-induced osteoporosis across a wide range of patients.

Non-pharmacological management of osteoporosis: a consensus of the Belgian Bone Club.

This consensus article reviews the various aspects of the non-pharmacological management of osteoporosis, including the effects of nutriments, physical exercise, lifestyle, fall prevention, and hip protectors. Vertebroplasty is also briefly reviewed. Non-pharmacological management of osteoporosis is a broad concept. It must be viewed as an essential part of the prevention of fractures from childhood through adulthood and the old age. The topic also includes surgical procedures for the treatment of peripheral and vertebral fractures and the post-fracture rehabilitation. The present document is the result of a consensus, based on a systematic review and a critical appraisal of the literature. Diets deficient in calcium, proteins or vitamin D impair skeletal integrity. The effect of other nutriments is less clear, although an excessive consumption of sodium, caffeine, or fibres exerts negative effects on calcium balance. The deleterious effects of tobacco, excessive alcohol consumption and a low BMI are well accepted. Physical activity is of primary importance to reach optimal peak bone mass but, if numerous studies have shown the beneficial effects of various types of exercise on bone mass, fracture data as an endpoint are scanty. Fall prevention strategies are especially efficient in the community setting, but less evidence is available about their effectiveness in preventing fall-related injuries and fractures. The efficacy of hip protectors remains controversial. This is also true for vertebroplasty and kyphoplasty. Several randomized controlled studies had reported a short-term advantage of vertebroplasty over medical treatment for pain relief, but these findings have been questioned by recent sham-controlled randomized clinical studies.

A FRAX® model for the assessment of fracture probability in Belgium.

UNLABELLED: A country-specific FRAX® model was developed from the epidemiology of fracture and death in Belgium. Fracture probabilities were identified that corresponded to currently accepted reimbursement thresholds. INTRODUCTION: The objective of this study was to evaluate a Belgian version of the WHO fracture risk assessment (FRAX®) tool to compute 10-year probabilities of osteoporotic fracture in men and women. A particular aim was to determine fracture probabilities that corresponded to the reimbursement policy for the management of osteoporosis in Belgium and the clinical scenarios that gave equivalent fracture probabilities. METHODS: Fracture probabilities were computed from published data on the fracture and death hazards in Belgium. Probabilities took account of age, sex, the presence of clinical risk factors and femoral neck bone mineral density (BMD). Fracture probabilities were determined that were equivalent to intervention (reimbursement) thresholds currently used in Belgium. RESULTS: Fracture probability increased with age, lower BMI, decreasing BMD T-score and all clinical risk factors used alone or combined. The 10-year probabilities of a major osteoporosis-related fracture that corresponded to current reimbursement guidelines ranged from approximately 7.5% at the age of 50 years to 26% at the age of 80 years where a prior fragility fracture was used as an intervention threshold. For women at the threshold of osteoporosis (femoral neck T-score = -2.5 SD), the respective probabilities ranged from 7.4% to 15%. Several combinations of risk-factor profiles were identified that gave similar or higher fracture probabilities than those currently accepted for reimbursement in Belgium. CONCLUSIONS: The FRAX® tool has been used to identify possible thresholds for therapeutic intervention in Belgium, based on equivalence of risk with current guidelines. The FRAX® model supports a shift from the current DXA-based intervention strategy, towards a strategy based on fracture probability of a major osteoporotic fracture that in turn may improve identification of patients at increased fracture risk. The approach will need to be supported by health economic analyses.

Evidence-based guidelines for the pharmacological treatment of postmenopausal osteoporosis: a consensus document by the Belgian Bone Club.

Several drugs are available for the management of postmenopausal osteoporosis. This may, in daily practice, confuse the clinician. This manuscript offers an evidence-based update of previous treatment guidelines, with a critical assessment of the currently available efficacy data on all new chemical entities which were granted a marketing authorization. Osteoporosis is widely recognized as a major public health concern. The availability of new therapeutic agents makes clinical decision-making in osteoporosis more complex. Nation-specific guidelines are needed to take into consideration the specificities of each and every health care environment. The present manuscript is the result of a National Consensus, based on a systematic review and a critical appraisal of the currently available literature. It offers an evidence-based update of previous treatment guidelines, with the aim of providing clinicians with an unbiased assessment of osteoporosis treatment effect.

The need for a transparent, ethical, and successful relationship between academic scientists and the pharmaceutical industry: a view of the Group for the Respect of Ethics and Excellence in Science (GREES).

UNLABELLED: This paper provides recommendations for fair and unbiased relationship between academic scientists and the pharmaceutical industry. INTRODUCTION: Real or perceived problems in the relationship between academics and the industry have been the subject of much recent debate. It has been suggested that academic clinicians should sever all links with the industry-a view that is rarely challenged. METHODS: Academic experts and members of the pharmaceutical industry were invited to an expert consensus meeting to debate this topic. This meeting was organized by the Group for the Respect of Ethics and Excellence in Science. Conflict of interest, competing interest, right and duties of academic scientist, authorship, and staff and student education were discussed. RESULTS: Guidelines for a transparent, ethical, strong, and successful partnership between the academic scientist and the pharmaceutical industry have been provided. CONCLUSIONS: The Group support interactions between the industry and clinicians provided that it is transparent and ethical.

Does orthodontic loading influence bone mineral density around titanium miniplates? An experimental study in dogs.

OBJECTIVES: To evaluate whether orthodontic loading has an effect on miniplate stability and bone mineral density (BMD) around the screws supporting those miniplates. SETTING AND SAMPLE POPULATION: Two miniplates were inserted in each jaw quadrant of 10 dogs. MATERIAL AND METHODS: Two weeks later, coil springs were placed between the miniplates of one upper quadrant and between those of the contralateral lower quadrant. The other miniplates remained non-loaded. The dogs were sacrificed 7 or 29 weeks after surgery, and the jaws were scanned with peripheral Quantitative Computed Tomography (pQCT) to assess BMD. RESULTS: The success rate was not significantly different for the loaded and the non-loaded miniplates, but was significantly higher for the maxillary compared to the mandibular ones. Mobility, associated with local inflammation, most often occurred during the transition between primary and secondary stability. pQCT showed higher BMD around mandibular vs. maxillary screws, without significant difference between loaded and non-loaded ones. Furthermore, load direction did not lead to any significant difference in BMD. CONCLUSION: Miniplate stability and BMD of the adjacent bone did not appear to depend significantly on orthodontic loading, but rather on the receptor site anatomy.

Loading and skeletal development and maintenance.

Mechanical loading is a major regulator of bone mass and geometry. The osteocytes network is considered the main sensor of loads, through the shear stress generated by strain induced fluid flow in the lacuno-canalicular system. Intracellular transduction implies several kinases and phosphorylation of the estrogen receptor. Several extra-cellular mediators, among which NO and prostaglandins are transducing the signal to the effector cells. Disuse results in osteocytes apoptosis and rapid imbalanced bone resorption, leading to severe osteoporosis. Exercising during growth increases peak bone mass, and could be beneficial with regards to osteoporosis later in life, but the gain could be lost if training is abandoned. Exercise programs in adults and seniors have barely significant effects on bone mass and geometry at least at short term. There are few data on a possible additive effect of exercise and drugs in osteoporosis treatment, but disuse could decrease drugs action. Exercise programs proposed for bone health are tedious and compliance is usually low. The most practical advice for patients is to walk a minimum of 30 to 60 minutes per day. Other exercises like swimming or cycling have less effect on bone, but could reduce fracture risk indirectly by maintaining muscle mass and force.

Management of osteoporosis in the elderly.

BACKGROUND: Osteoporosis is predominantly a condition of the elderly, and the median age for hip fracture in women is approximately 83 years. Osteoporotic fracture risk is multifactorial, and often involves the balance between bone strength and propensity for falling. OBJECTIVE: To present an overview of the available evidence, located primarily by Medline searches up to April, 2009, for the different management strategies aimed at reducing the risk of falls and osteoporotic fractures in the elderly. RESULTS: Frailty is an independent predictor of falls, hip fractures, hospitalisation, disability and death in the elderly that is receiving increasing attention. Non-pharmacological strategies to reduce fall risk can prevent osteoporotic fractures. Exercise programmes, especially those involving high doses of exercise and incorporating balance training, have been shown to be effective. Many older people, especially the very elderly and those living in care institutions, have vitamin D inadequacy. In appropriate patients and given in sufficient doses, vitamin D and calcium supplementation is effective in reducing both falls and osteoporotic fractures, including hip fractures. Specific anti-osteoporosis drugs are underused, even in those most at risk of osteoporotic fracture. The evidence base for the efficacy of most such drugs in the elderly is incomplete, particularly with regard to nonvertebral and hip fractures. The evidence base is perhaps most complete for the relatively recently introduced drug, strontium ranelate. Non-adherence to treatment is a substantial problem, and may be exacerbated by the requirements for safe oral administration of bisphosphonates. CONCLUSION: Evidence-based strategies are available for reducing osteoporotic fracture risk in the elderly, and include exercise training, vitamin D and calcium supplementation, and use of evidence-based anti-osteoporotic drugs. A positive and determined approach to optimising the use of such strategies could reduce the burden of osteoporotic fractures in this high-risk group.

Long-term treatment of postmenopausal osteoporosis with strontium ranelate: results at 8 years.

OBJECTIVES: Strontium ranelate 2 g/day has proven efficacy against vertebral and nonvertebral fracture over 5 years in postmenopausal osteoporosis, though many women require longer-term treatment. This article describes the efficacy, safety, and tolerability of this agent over 8 years. METHODS: Postmenopausal osteoporotic women having participated in the 5-year efficacy trials SOTI and TROPOS were invited to enter a 3-year open-label extension study. The results presented here focus on patients who received strontium ranelate for 8 years. RESULTS: At the extension baseline, the population treated for 8 years (n=879; 79.1+/-5.6 years) had femoral neck T-score of -2.61+/-0.71. The cumulative incidences of new vertebral and nonvertebral fractures (13.7% and 12.0%, respectively) over years 6 to 8 were non-statistically different from the cumulative incidences in the first 3 years of the original studies (11.5% and 9.6%). Lumbar spine, femoral neck, and total hip bone mineral density (BMD) increased throughout the 8-year period. Annual relative change in BMD was significant at every visit, except the 8-year visit for femoral neck and total hip BMD. Strontium ranelate was safe and well tolerated over 8 years. CONCLUSIONS: Long-term treatment with strontium ranelate 2 g/day in postmenopausal osteoporotic women leads to continued increases in BMD at all sites. The data also provide some evidence for a sustained antifracture efficacy.

Evidence-based guidelines for the use of biochemical markers of bone turnover in the selection and monitoring of bisphosphonate treatment in osteoporosis: a consensus document of the Belgian Bone Club.

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.

[A FRAX model for the assessment of fracture probability in Belgium]. / Rationalisation du remboursement des médicaments de l'ostéoporose: de la mesure isolée de la densité osseuse i l'intégration des facteurs cliniques de risque fracturaire. Validation de l'algorithme FRAX.

The objective of this study was to evaluate a Belgian version of the WHO fracture risk assessment (FRAX) tool to compute 10-year probabilities of osteoporotic fracture in men and women. A particular aim was to determine fracture probabilities that corresponded to the reimbursement policy for the management of osteoporosis in Belgium and the clinical scenarios that gave equivalent fracture probabilities. Fracture probabilities were computed from published data on the fracture and death hazards in Belgium. Probabilities took account of age, sex, the presence of clinical risk factors and femoral neck BMD. Fracture probabilities were determined that were equivalent to intervention (reimbursement) thresholds currently used in Belgium. Fracture probability increased with age, lower BMI, decreasing BMD T-Score, and all clinical risk factors used alone or combined. The FRAX tool has been used to identify possible thresholds for therapeutic intervention in Belgium, based on equivalence of risk with current guidelines. The FRAX model supports a shift from the current DXA based intervention strategy, towards a strategy based on fracture probability of a major osteoporotic fracture that in turn may improve identification of patients at increased fracture risk. The approach will need to be supported by health economic analyses.

Fluoride effects on bone formation and mineralization are influenced by genetics.

INTRODUCTION: A variation in bone response to fluoride (F(-)) exposure has been attributed to genetic factors. Increasing fluoride doses (0 ppm, 25 ppm, 50 ppm, 100 ppm) for three inbred mouse strains with different susceptibilities to developing dental enamel fluorosis (A/J, a "susceptible" strain; SWR/J, an "intermediate" strain; 129P3/J, a "resistant" strain) had different effects on their cortical and trabecular bone mechanical properties. In this paper, the structural and material properties of the bone were evaluated to explain the previously observed changes in mechanical properties. MATERIALS AND METHODS: This study assessed the effect of increasing fluoride doses on the bone formation, microarchitecture, mineralization and microhardness of the A/J, SWR/J and 129P3/J mouse strains. Bone microarchitecture was quantified with microcomputed tomography and strut analysis. Bone formation was evaluated by static histomorphometry. Bone mineralization was quantified with backscattered electron (BSE) imaging and powder X-ray diffraction. Microhardness measurements were taken from the vertebral bodies (cortical and trabecular bones) and the cortex of the distal femur. RESULTS: Fluoride treatment had no significant effect on bone microarchitecture for any of the strains. All three strains demonstrated a significant increase in osteoid formation at the largest fluoride dose. Vertebral body trabecular bone BSE imaging revealed significantly decreased mineralization heterogeneity in the SWR/J strain at 50 ppm and 100 ppm F(-). The trabecular and cortical bone mineralization profiles showed a non-significant shift towards higher mineralization with increasing F(-) dose in the three strains. Powder X-ray diffraction showed significantly smaller crystals for the 129P3/J strain, and increased crystal width with increasing F(-) dose for all strains. There was no effect of F(-) on trabecular and cortical bone microhardness. CONCLUSION: Fluoride treatment had no significant effect on bone microarchitecture in these three strains. The increased osteoid formation and decreased mineralization heterogeneity support the theory that F(-) delays mineralization of new bone. The increasing crystal width with increasing F(-) dose confirms earlier results and correlates with most of the decreased mechanical properties. An increase in bone F(-) may affect the mineral-organic interfacial bonding and/or bone matrix proteins, interfering with bone crystal growth inhibition on the crystallite faces as well as bonding between the mineral and organic interface. The smaller bone crystallites of the 129P3/J (resistant) strain may indicate a stronger organic/inorganic interface, reducing crystallite growth rate and increasing interfacial mechanical strength.

Strontium ranelate reduces the risk of vertebral fracture in young postmenopausal women with severe osteoporosis.

OBJECTIVES: Early osteoporotic fractures have a great impact on disease progression, the first fracture being a major risk factor for further fractures. Strontium ranelate efficacy against vertebral fractures is presently assessed in a subset of women aged 50-65 years. METHODS: The Spinal Osteoporosis Therapeutic Intervention (SOTI) was an international, double blind, placebo controlled trial, supporting the efficacy of strontium ranelate 2 g/day in reducing the risk of vertebral fractures in postmenopausal women with osteoporosis and a prevalent vertebral fracture. 353 of these randomly assigned women were included in this analysis. RESULTS: Over 4 years, strontium ranelate significantly reduced the risk of vertebral fracture by 35% (relative risk 0.65; 95% CI 0.42 to 0.99, p<0.05). In the strontium ranelate group, the bone mineral density increased from baseline by 15.8% at lumbar spine and 7.1% at femoral neck. CONCLUSION: These data demonstrate a significant vertebral antifracture efficacy of strontium ranelate in young postmenopausal women aged 50-65 years with severe osteoporosis and confirm the efficacy of this antiosteoporotic treatment to prevent vertebral fractures, whatever the age of the patient.