Management of osteoporosis of the oldest old.

UNLABELLED: This consensus article reviews the diagnosis and treatment of osteoporosis in geriatric populations. Specifically, it reviews the risk assessment and intervention thresholds, the impact of nutritional deficiencies, fall prevention strategies, pharmacological treatments and their safety considerations, the risks of sub-optimal treatment adherence and strategies for its improvement. INTRODUCTION: This consensus article reviews the therapeutic strategies and management options for the treatment of osteoporosis of the oldest old. This vulnerable segment (persons over 80 years of age) stands to gain substantially from effective anti-osteoporosis treatment, but the under-prescription of these treatments is frequent. METHODS: This report is the result of an ESCEO (European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis) expert working group, which explores some of the reasons for this and presents the arguments to counter these beliefs. The risk assessment of older individuals is briefly reviewed along with the differences between some intervention guidelines. The current evidence on the impact of nutritional deficiencies (i.e. calcium, protein and vitamin D) is presented, as are strategies to prevent falls. One possible reason for the under-prescription of pharmacological treatments for osteoporosis in the oldest old is the perception that anti-fracture efficacy requires long-term treatment. However, a review of the data shows convincing anti-fracture efficacy already by 12 months. RESULTS: The safety profiles of these pharmacological agents are generally satisfactory in this patient segment provided a few precautions are followed. CONCLUSION: These patients should be considered for particular consultation/follow-up procedures in the effort to convince on the benefits of treatment and to allay fears of adverse drug reactions, since poor adherence is a major problem for the success of a strategy for osteoporosis and limits cost-effectiveness.

Tools in the assessment of sarcopenia.

This review provides a framework for the development of an operational definition of sarcopenia and of the potential end points that might be adopted in clinical trials among older adults. While the clinical relevance of sarcopenia is widely recognized, there is currently no universally accepted definition of the disorder. The development of interventions to alter the natural history of sarcopenia also requires consensus on the most appropriate end points for determining outcomes of clinical importance which might be utilized in intervention studies. We review current approaches to the definition of sarcopenia and the methods used for the assessment of various aspects of physical function in older people. The potential end points of muscle mass, muscle strength, muscle power, and muscle fatigue, as well as the relationships between them, are explored with reference to the availability and practicality of the available methods for measuring these end points in clinical trials. Based on current evidence, none of the four potential outcomes in question is sufficiently comprehensive to recommend as a uniform single outcome in randomized clinical trials. We propose that sarcopenia may be optimally defined (for the purposes of clinical trial inclusion criteria as well as epidemiological studies) using a combination of measures of muscle mass and physical performance. The choice of outcome measures for clinical trials in sarcopenia is more difficult; co-primary outcomes, tailored to the specific intervention in question, may be the best way forward in this difficult but clinically important area.

Health claims assessment in the field of joint and cartilage: a consensus viewpoint of the Group for the Respect of Ethics and Excellence in Science.

INTRODUCTION: In 2006, the European Parliament and Council issued a regulation (No. 1924/2006) for the nutrition and health claims made on foods, including food supplements. According to the regulation, the use of nutrition and health claims shall only be permitted if the substance in respect of which the claim is made has been shown to have a beneficial nutritional or physiological effect. In the field of joint and cartilage health, there is no clear scientific-based definition of the nature of such a beneficial nutritional or physiological effect. The objective of this paper is to scientifically define the possible content of health claims related to joint and cartilage health and to provide scientific guidelines for the design of clinical studies which need to be adopted to substantiate such health claims. METHODS: Literature review up to September 2011 followed by a consensus expert discussion organized by the Group for the Respect of Ethics and Excellence in Science (GREES). RESULTS: In line with the general principles of the PASSCLAIM and the Codex recommendations, the GREES identified four acceptable health claims related to joint and cartilage health based on the effects on discomfort, joint and cartilage structural integrity or risk factors for joint and cartilage diseases. The GREES considers that randomized controlled trials on a relevant outcome is the best design to assess health claims. Moreover, animal studies could also be of interest to substantiate some health claims, to assess the clinical relevance of endpoints used in human studies or to extrapolate data obtained in patients to the target (apparently) healthy population. CONCLUSION: According to the methodology and biomarkers used in the study and whether or not additional animal studies are provided to support the claim, various health claims can be acceptable in the field of joint and cartilage health.

Implications for fracture healing of current and new osteoporosis treatments: an ESCEO consensus paper.

Osteoporotic fracture healing is critical to clinical outcome in terms of functional recovery, morbidity, and quality of life. Osteoporosis treatments may affect bone repair, so insights into their impact on fracture healing are important. We reviewed the current evidence for an impact of osteoporosis treatments on bone repair. Treatment with bisphosphonate in experimental models is associated with increased callus size and mineralization, reduced callus remodeling, and improved mechanical strength. Local and systemic bisphosphonate treatment may improve implant fixation. No negative impact on fracture healing has been observed, even after major surgery or when administered immediately after fracture. Experimental data for denosumab and raloxifene suggest no negative implications for bone repair. The extensive experimental results for teriparatide indicate increased callus formation, improved biomechanical strength, and greater external callus volume and total bone mineral content and density. Case reports and a randomized trial have produced mixed results but are consistent with a positive impact of teriparatide on clinical fracture healing. Studies with strontium ranelate in models of fracture healing indicate that it is associated with improved bone microstructure, callus volume, and biomechanical properties. Finally, there is experimental evidence for a beneficial effect of some of the agents currently being developed for osteoporosis, notably sclerostin antibody and DKK1 antibody. There is currently no evidence that osteoporosis treatments are detrimental for bone repair and some promising experimental evidence for positive effects on healing, notably for agents with a bone-forming mode of action, which may translate into therapeutic applications.

Frailty and sarcopenia: definitions and outcome parameters.

An operational definition of musculoskeletal decline in older people is needed to allow development of interventions for prevention or treatment, as was developed for the treatment of osteoporosis. Frailty and sarcopenia are linked, but distinct, correlates of musculoskeletal aging that have many causes, including age-related changes in body composition, inflammation, and hormonal imbalance. With the emergence of a number of exciting candidate therapies to retard the loss of muscle mass with aging, the derivation of a consensual definition of sarcopenia and physical frailty becomes an urgent priority. Although several consensual definitions have been proposed, these require clinical validation. An operational definition, which might provide a threshold for treatment/trial inclusion, should incorporate a loss of muscle mass as well as evidence of a decrease in muscle strength and/or physical activity. Evidence is required for a link between improvements in the measures of muscle strength and/or physical activity and clinical outcomes to allow development of interventions to improve clinical outcomes in frail older patients.

Assessment of health claims in the field of bone: a view of the Group for the Respect of Ethics and Excellence in Science (GREES).

UNLABELLED: Health claims for food products in Europe are permitted if the nutrient has been shown to have a beneficial nutritional or physiological effect. This paper defines health claims related to bone health and provides guidelines for the design and the methodology of clinical studies to support claims. INTRODUCTION: Regulation (EC) no. 1924/2006 on nutrition and health claims targeting food products was introduced in Europe stating that health claims shall only be permitted if the substance in respect of which the claim is made has been shown to have a beneficial nutritional or physiological effect. The objective of this paper is to define health claims related to bone health and to provide guidelines for the design and the methodology of clinical studies which need to be adopted to assert such health claims. METHODS: Literature review followed by a consensus discussion during two 1-day meetings organized by the Group for the Respect of Ethics and Excellence in Science (GREES). RESULTS: The GREES identified six acceptable health claims related to bone health based on the potential of food products to show an effect on either the bioavailability of calcium or osteoclast regulatory proteins or bone turnover markers or bone mineral density or bone structure or fracture incidence. The GREES considers that well-designed human randomized controlled trial on a relevant outcome is the best design to assess health claims. The substantiation of health claim could also be supported by animal studies showing either an improvement in bone strength with the food product or showing the relationship between changes induced by the food product on a surrogate marker and changes in bone strength. CONCLUSION: The consensus reached is that the level of health claim may differ according to the surrogate endpoint used and on additional animal studies provided to support the claim.

Biomarkers and personalised medicine in rheumatoid arthritis: a proposal for interactions between academia, industry and regulatory bodies.

Rheumatoid arthritis (RA) is one of the most appropriate conditions for the application of personalised medicine as a high degree of heterogeneity has been recognised, which remains to be explained. Such heterogeneity is also reflected in the large number of treatment targets and options. A growing number of biologics as well as small molecules are already in use and there are promising new drugs in development. In order to make the best use of treatment options, both targeted and non-targeted biomarkers have to be identified and validated. To this aim, new rules are needed for the interaction between academia and industry under regulatory control. Setting up multi-centre biosample collections with clear definition of access, organising early, possibly non-committing discussions with regulatory authorities, and defining a clear route for the validation, qualification and registration of the biomarker-drug combination are some of the more critical areas where effective collaboration between the drug industry, academia and regulators is needed.

Adherence to treatment of osteoporosis: a need for study.

UNLABELLED: Adherence to anti-osteoporosis medications is currently low and is associated with poor anti-fracture efficacy. This manuscript reviews the potential design of clinical studies that aim to demonstrate improved adherence, with new chemical entities to be used in the management of osteoporosis. INTRODUCTION: Several medications have been unequivocally shown to decrease fracture rates in clinical trials. However, in real life settings, long-term persistence and compliance to anti-osteoporosis medication is poor, hence decreasing the clinical benefits for patients. METHODS: An extensive search of Medline from 1985 to 2006 retrieved all trials including the keywords osteoporosis, compliance, persistence or adherence followed by a critical appraisal of the data obtained through a consensus expert meeting. RESULTS: The impact of non-adherence on the clinical development of interventions is reviewed, so that clinicians, regulatory agencies and reimbursement agencies might be better informed of the problem, in order to stimulate the necessary research to document adherence. CONCLUSION: Adherence to therapy is a major problem in the treatment of osteoporosis. Both patients and medication factors are involved. Adherence studies are an important aspect of outcomes studies, but study methodologies are not well developed at the moment and should be improved. Performing adherence studies will be stimulated when registration authorities accept the result of these studies and include the relevant information in Sect. 5.1 of the summary of product characteristics. Reimbursement authorities might also consider such studies as important information for decisions on reimbursement.

S12911-2 reduces bone loss induced by short-term immobilization in rats.

Skeletal immobilization induces trabecular bone loss resulting from increased bone resorption and decreased formation. In this study we determined the effect of S12911-2, a compound containing two atoms of stable strontium, on trabecular bone loss induced by short-term immobilization of hind limbs in rats. Male Sprague-Dawley rats were randomly allocated to six groups (n = 25 per group). At 9 weeks of age, five groups of rats had their right hind limb immobilized for 10 days, using a plaster cast, whereas one control group was not immobilized (CT). Four groups of immobilized rats were treated for 10 days with 50, 200, or 800 mg/kg/day of S12911-2 or the vehicle. One group of immobilized rats was pretreated (PT) for 2 weeks with 200 mg/kg/day of S12911-2 and continued treatment during the immobilization period. Immobilization of the right hind limb induced bone loss as shown by decreased ash weight (-12%) and bone mineral density measured by dual energy x-ray absorptiometry of the femur (-9%), and confirmed by decreased trabecular bone volume measured by histomorphometry of the tibial metaphysis (-25%). This effect was unrelated to alteration in long bone length and was associated with increased urinary hydroxyproline excretion (+12%), increased osteoclast surface and number (+27%), decreased mineral apposition rate (-30%), and tetracycline double labeled surface (-17%) in the immobilized tibia. S12911-2 (800 mg/kg/day) partially reduced bone loss, as shown by increased bone mineral density (+4%) and trabecular bone volume (+19%) compared with untreated immobilized rats. Furthermore, S12911-2 (800 mg/kg/day) increased bone density (+5%) in the contralateral nonimmobilized leg. These effects resulted from inhibition of bone resorption, as shown by normalization of urinary hydroxyproline excretion and histomorphometric indices of bone resorption. This study shows that the bone resorption induced by immobilization in rats can be suppressed by treatment with S12911-2, resulting in partial reduction of the bone loss.

S 12911-2 inhibits osteoclastic bone resorption in vitro.

The potential anti-osteoporotic activity of the strontium compound, S12911, was tested on osteoclast-like cells and on cultured fetal mouse long bones. From 1 mM Sr2+, S12911 reduced both basal and stimulated bone resorption by decreasing osteoclast activity and ruffled border formation. The aim of this study was to evaluate the effects of S 12911-2 on osteoclastic bone resorption using in vitro systems. Osteoclast-like cells, produced in vitro by co-culture of mouse bone marrow cells with primary osteoblasts, were allowed to settle on dentine slices, and the area of resorption pits formed after 48 h was measured using an image analysis system. S 12911-2, at a minimal active concentration of 1 mM Sr2+, significantly reduced pit formation by these cells (p < 0.05). Pretreatment of slices for 48 h with S 12911-2 (5 mM Sr2+) did not produce appreciable inhibition of resorption. Bone resorption in cultured fetal mouse long bones was assessed by measuring the release of pre-incorporated 45calcium. S 12911-2 inhibited resorption in control cultures (18.9%, p < or = 0.05) and in bones cultured with the active form of vitamin D3 [1,25(OH)2D3] (44.5%, p < or = 0.05). S 12911-2 had no effect on the number of osteoclasts observed histochemically in longitudinal sections prepared from fetal mouse long bones. Electron microscopy of mouse long bones treated with S 12911-2 (3 mM Sr2+) showed osteoclasts with clear zones facing the bone surface, but without well-developed ruffled borders; untreated bones contained osteoclasts with normal ruffled borders. These results indicate that S 12911-2 inhibits osteoclast activity. This effect is directly linked to the presence of strontium, is effective on basal and stimulated resorption, and involves a decrease in ruffled border formation by osteoclasts.

Strontium ranelate inhibits bone resorption while maintaining bone formation in alveolar bone in monkeys (Macaca fascicularis).

Strontium ranelate (S12911) has previously been shown to stimulate bone formation and inhibit bone resorption in rats. To determine whether strontium ranelate affects normal bone remodeling, we studied the effect of strontium ranelate on alveolar bone in monkeys. Strontium ranelate, at dosages of 100, 275, and 750 mg/kg per day, or vehicle, were given by gavage to 31 normal adult monkeys (Macaca fascicularis) (15 males, 16 females), aged 3-4 years. Treatment for 6 months with strontium ranelate resulted in an increase in plasma strontium concentration. Histomorphometric analyses of indices of bone formation and resorption were determined in standardized areas of alveolar bone. Treatment with strontium ranelate decreased the histomorphometric indices of bone resorption (osteoclast surface and number) with a maximal significant effect at the highest dose tested. In contrast to this inhibitory effect on bone resorption, strontium ranelate maintained bone formation. Although the amount of osteoid tended to increase, strontium ranelate, even at the highest dose, had no deleterious effect on bone mineralization, as evaluated by mineral apposition rate and osteoid thickness. These findings show that strontium ranelate decreases indices of bone resorption while maintaining bone formation in the alveolar bone in monkeys.

Incorporation and distribution of strontium in bone.

The distribution and incorporation of strontium into bone has been examined in rats, monkeys, and humans after oral administration of strontium (either strontium chloride or strontium ranelate). After repeated administration for a sufficient period of time (at least 4 weeks in rats), strontium incorporation into bone reaches a plateau level. This plateau appears to be lower in females than in males due to a difference in the absorption process. Steady-state plasma strontium levels are reached more rapidly than in bones, and within 10 days in the rat. The strontium levels in bone vary according to the anatomical site. However, strontium levels at different skeletal sites are strongly correlated, and the strontium content of the lumbar vertebra may be estimated from iliac crest bone biopsies in monkeys. The strontium levels in bone also vary according to the bone structure and higher amounts of strontium are found in cancellous bone than in cortical bone. Furthermore, at the crystal level, higher concentrations of strontium are observed in newly formed bone than in old bone. After withdrawal of treatment, the bone strontium content rapidly decreases in monkeys. The relatively high clearance rate of strontium from bone can be explained by the mechanisms of its incorporation. Strontium is mainly incorporated by exchange onto the crystal surface. In new bone, only a few strontium atoms may be incorporated into the crystal by ionic substitution of calcium. After treatment withdrawal, strontium exchanged onto the crystal is rapidly eliminated, which leads to a rapid decrease in total bone strontium levels. In summary, incorporation of strontium into bone, mainly by exchange onto the crystal surface, is dependent on the duration of treatment, dose, gender, and skeletal site. Nevertheless, bone strontium content is highly correlated with plasma strontium levels and, in bone, between the different skeletal sites.

Strontium ranelate increases cartilage matrix formation.

Based on previous studies showing that strontium ranelate (S12911) modulates bone loss in osteoporosis, it could be hypothesized that this drug also is effective on cartilage degradation in osteoarthritis (OA). This was investigated in vitro on normal and OA human chondrocytes treated or not treated with interleukin-1beta (IL-1beta). This model mimics, in vitro, the imbalance between chondroformation and chondroresorption processes observed in vivo in OA cartilage. Chondrocytes were isolated from cartilage by enzymatic digestion and cultured for 24-72 h with 10(-4)-10(-3) M strontium ranelate, 10(-3) M calcium ranelate, or 2 x 10(-3) M SrCl2 with or without IL-1beta or insulin-like growth factor I (IGF-I). Stromelysin activity and stromelysin quantitation were assayed by spectrofluorometry and enzyme amplified sensitivity immunoassay (EASIA), respectively. Proteoglycans (PG) were quantified using a radioimmunoassay. Newly synthesized glycosaminoglycans (GAGs) were quantified by labeled sulfate (Na2(35)SO4) incorporation. This method allowed the PG size after exclusion chromatography to be determined. Strontium ranelate, calcium ranelate, and SrCl2 did not modify stromelysin synthesis even in the presence of IL-1beta. Calcium ranelate induced stromelysin activation whereas strontium compounds were ineffective. Strontium ranelate and SrCl2 both strongly stimulated PG production suggesting an ionic effect of strontium independent of the organic moiety. Moreover, 10(-3) M strontium ranelate increased the stimulatory effect of IGF-I (10(-9) M) on PG synthesis but did not reverse the inhibitory effect of IL-1beta. Strontium ranelate strongly stimulates human cartilage matrix formation in vitro by a direct ionic effect without stimulating the chondroresorption processes. This finding provides a preclinical basis for in vivo testing of strontium ranelate in OA.

Effects of intranasal 17beta-estradiol on bone turnover and serum insulin-like growth factor I in postmenopausal women.

Estrogen therapy, using either oral or transdermal routes, decreases bone turnover and prevents postmenopausal bone loss. It has been suggested that oral and transdermal 17beta-estradiol (E2) may have different effects on serum insulin-like growth factor I (IGF-I), a potent bone-forming growth factor. In this study we investigated the effects of a new route of administration, the intranasal E2 spray (S21400), on bone turnover and circulating IGF-I and IGF-binding protein-3 (IGFBP-3). Four hundred and twenty early postmenopausal women (<5 yr since menopause; mean age, 52 yr) were enrolled in a 3-month, double blind, placebo-controlled study of four doses of intranasal E2 (100, 200, 300, and 400 microg/day), two doses of oral E2 valerate (1 or 2 mg/day), and placebo. One hundred and twelve women were further treated for 12 months with intranasal E2 (300 microg/day, i.e. the dose that has been shown to be adequate for the majority of postmenopausal women). Markers of bone resorption (urinary type I collagen C telopeptides) and formation [serum osteocalcin, serum type I collagen N-terminal extension propeptide (PINP), and serum bone alkaline phosphatase (BAP)] were measured at baseline, 1 month, 3 months, and 15 months. Serum IGF-I and IGFBP-3 were measured at baseline, 1 month, and 3 months. Urinary type I collagen C telopeptides decreased significantly in all active treatment groups as soon as 1 month (P<0.001 vs. placebo) and continued to decrease at 3 months with a dose effect for intranasal E2. Serum osteocalcin and PINP did not change at 1 month for oral E2 (1 and 2 mg), but decreased significantly at 3 months. In contrast, formation markers increased significantly at 1 month for the two highest doses of intranasal E2 (P<0.01 vs. placebo for osteocalcin and BAP) and did not decrease at 3 months. Oral E2 induced a marked decrease in circulating IGF-I as early as 1 month, which was amplified at 3 months (-29% and -32% for 1 and 2 mg, respectively), whereas no significant change from placebo was observed for intranasal E2 during the 3-month period. Changes in circulating IGF-I correlated significantly (P<0.01) with changes in osteocalcin, PINP, and BAP at 3 months. Oral and intranasal E2 did not induce any significant change from placebo in serum IGFBP-3 at both 1 and 3 months. After 1 yr of treatment with intranasal E2 (300 microg/day), both resorption and formation markers decreased, reaching the levels in premenopausal women, regardless of the type of treatment during the first 3 months. We conclude that E2 administered by this new nasal route normalizes bone turnover to premenopausal levels. The delayed decrease in bone formation observed with intranasal E2 compared to oral E2 may be related to different effects on serum IGF-I levels.

Efficacy and acceptability of intranasal 17 beta-oestradiol for menopausal symptoms: randomised dose-response study. Aerodiol Study Group.

BACKGROUND: The benefit of oestrogen therapy for menopause symptoms is well recognised. However, the means of delivery currently available have disadvantages, including variable bioavailability, intestinal and hepatic first-pass effects, and dermatological reactions. An intranasal 17beta-oestradiol spray, S21400, which bypasses such drawbacks, has been developed. We studied the efficacy and tolerability of S21400 in the treatment of postmenopausal symptoms. METHODS: In this double-blind study, 420 postmenopausal women were randomly allocated to receive intranasal placebo or S21400 in doses of 100 microg, 200 microg, 300 microg, or 400 microg, or oral oestradiol valerate in doses of 1 mg or 2 mg, daily for 12 weeks. The primary outcomes were the Kupperman Index (KI) and the incidence of hot flushes. Tolerability assessments included rhinoscopy and ciliary function tests. FINDINGS: S21400 dose-dependently decreased KI (p<0.001), with a lowest effective dose of 300 microg/day at 4 weeks (p<0.05) and 200 microg/day at 12 weeks (p<0.01). The incidence of hot flushes decreased by a maximum of 75% (S21400 lowest effective dose 200 microg/day at 4 weeks and 100 microg/day at 12 weeks). S21400 increased serum oestradiol exposure dose-dependently, to concentrations similar to those achieved with oral oestradiol 1-2 mg, with lower intra-patient and inter-patient variability. There was no significant difference in ear, nose, and throat function or adverse events between the S21400 and the placebo or oral oestradiol groups, except for a greater incidence of sneezing and application site reaction (99% mild or moderate) in the S21400 groups. S21400 was thought to be effective and convenient by the patients, and compliance was high. INTERPRETATION: Intranasally administered 17beta-oestradiol is significantly better than placebo; its effectiveness at reducing menopausal symptoms is similar to that of oral oestradiol and is also well-tolerated. Intranasal administration avoids first-pass metabolism and provides a reproducible, easily adjustable dosing mechanism that represents a new option for hormone replacement therapy.

The use of different dual X-ray absorptiometry brands in a multicenter clinical trial: consequences and limits.

Accurate cross-calibration (CC) and quality control (QC) programs for dual X-ray absorptiometry (DXA) instruments are necessary in order to guarantee appropriate measurements of bone mineral density (BMD) during longitudinal studies. This article details the CC-QC program established for the STRATOS study, a multicenter clinical trial investigating the effects of strontium ranelate on osteoporotic women with vertebral fractures. Forty-five DXA instruments of different brands (namely, 27 Hologic, 9 Lunar, 5 Norland, and 4 Sopha) were cross-calibrated at the beginning of the study. Twenty-seven of these were still in use by the end of the study. The CC was performed at the beginning and at the end of the study by measuring a unique spine phantom 20 times. The in vitro reproducibility of measurements. (coefficient of variation [CV]) was calculated from the results of the phantom measurements. The in vivo CV was obtained from pairs of measurements of the lumbar spine and the hip of the patients at the time of inclusion in the study. Initial in vitro CV averaged 0.5%. At the end of the study, the CC performed for the 27 apparatus in use at the end of the trial provided long-term intrabrand in vitro CV of 0.7% for the Hologic (n = 18), 1% for the Lunar (n = 5), and 0.3% for the Norland (n = 4) DXA instruments. The in vivo short-term CV for the lumbar spine BMD measurements was suboptimal, as opposed to the hip measurements, and was most likely due to the age of the population investigated. The results of measurements of multibrand DXA apparatus in this multicenter study suggest several practical conclusions: (1) the CC should be performed by using a single phantom independent of the DXA brand tested; (2) duplicate measurements should be performed at the time of patient inclusion; (3) the most efficient QC program should include CC, central reading of in vivo scans, and central review of daily QC.

Strontium distribution and interactions with bone mineral in monkey iliac bone after strontium salt (S 12911) administration.

The analysis of the interaction of strontium (Sr) with bone mineral is of interest because a new agent containing Sr (S 12911) has shown positive effects on bone mass in various animal models of osteoporosis and is currently being developed for preventive and curative treatment of postmenopausal osteoporosis. Iliac bone samples were obtained from 20 male monkeys: 4 untreated control animals, 12 animals sacrificed at the end of a 13-week treatment with high dose levels of S 12911 (750, 275, or 100 mg/kg/day orally), and 4 animals sacrificed 6 weeks after the end of a 13-week treatment with S 12911 (750 or 100 mg/kg/day orally). The distribution of Sr was determined and quantified by X-ray microanalysis. Changes at the crystal level were evaluated by X-ray diffraction and Raman microspectrometry. In the control animals, traces of Sr were found to be homogeneously distributed throughout the bone tissue. In the treated monkeys, Sr could only be detected in calcified matrix. In monkeys sacrificed at the end of the treatment, Sr was found to be dose-dependently incorporated into the mineral substance of the compact and cancellous bone. Sr was heterogeneously distributed with three to four times more Sr in new than in old compact bone, and approximately two and a half times more Sr in new than in old cancellous bone. The bone Sr content dramatically decreased in the animals sacrificed 6 weeks after the end of the treatment. Diffraction showed no significant changes in the characteristics of the crystal lattice. Sr appeared to be easily exchangeable from bone mineral and was slightly linked to mature crystals through ionic substitutions. Even at the highest dose level tested, less than 1 calcium ion out of 10 was substituted by 1 Sr ion in each crystal. In conclusion, taken up by bone, Sr was heterogeneously distributed with a higher concentration in new than in old bone but induced no major modifications of the bone mineral (crystallinity, crystal structure) at the crystal level. As a result, a treatment with S 12911 Sr salt should not induce any alteration of bone mineral.