Correction to: Hypophosphatasia: Canadian update on diagnosis and management.

In the article mentioned above an author's name was misspelled.

Hypophosphatasia: Canadian update on diagnosis and management.

Hypophosphatasia (HPP) is a rare inherited disorder of bone and mineral metabolism caused by loss of function mutations in the ALPL gene. The presentation in children and adults can be extremely variable and natural history is poorly understood particularly in adults. Careful patient evaluation is required with consideration of pharmacologic intervention in individuals meeting criteria for therapy. INTRODUCTION: The purposes of this review are to present current evidence regarding the diagnosis and management of hypophosphatasia in children and adults and provide evidence-based recommendations for management. METHOD: A MEDLINE, EMBASE, and Cochrane database search and literature review was completed. The following consensus recommendations were developed based on the highest level of evidence as well as expert opinion. RESULTS: Hypophosphatasia is a rare inherited disorder of bone and mineral metabolism due to loss of function mutations in the tissue non-specific alkaline phosphatase (ALPL) gene causing reductions in the activity of the tissue non-specific isoenzyme of alkaline phosphatase (TNSALP). Deficient levels of alkaline phosphatase result in elevation of inhibitors of mineralization of the skeleton and teeth, principally inorganic pyrophosphate. The impaired skeletal mineralization may result in elevations in serum calcium and phosphate. Clinical features include premature loss of teeth, metatarsal and subtrochanteric fractures as well as fragility fractures. Poor bone healing post fracture has been observed. Myalgias and muscle weakness may also be present. In infancy and childhood, respiratory and neurologic complications can occur. CONCLUSIONS: HPP is associated with significant morbidity and mortality. Pharmacologic intervention can result in significant clinical improvement. This Canadian position paper provides an overview of the musculoskeletal, renal, dental, respiratory, and neurologic manifestations of hypophosphatasia. The current state of the art in the diagnosis and management of hypophosphatasia is presented.

Mortality risk reduction differs according to bisphosphonate class: a 15-year observational study.

In this prospective cohort of 6120 participants aged 50+, nitrogen-bisphosphonates but not non-nitrogen bisphosphonates were associated with a significant 34% mortality risk reduction compared to non-treated propensity score matched controls. These findings open new avenues for research into mechanistic pathways. INTRODUCTION: Emerging evidence suggests that bisphosphonates (BP), first-line treatment of osteoporosis, are associated with reduced risks for all-cause mortality. This study aimed to determine the association between different BP types and mortality risk in participants with or without a fracture. METHODS: A prospective cohort study of users of different BPs matched to non-users by propensity score (age, gender, co-morbidities, fragility fracture status) and time to starting the BP medication from the population-based Canadian Multicentre Osteoporosis Study from nine Canadian centres followed from 1995 to 2013. Mortality risk for bisphosphonate users vs matched non-users was assessed using pairwise multivariable Cox proportional hazards models. RESULTS: There were 2048 women and 308 men on BP and 1970 women and 1794 men who did not receive medication for osteoporosis. The relationship between BP and mortality risk was explored in three separate 1:1 propensity score-matched cohorts of BP users and no treatment (etidronate, n = 599, alendronate, n = 498, and risedronate n = 213). Nitrogen BP (n-BP) (alendronate and risedronate) was associated with lower mortality risks [pairwise HR, 0.66 (95% CI, 0.48-0.91)] while the less potent non-n-BP, etidronate, was not [pairwise HR: 0.89 (95% CI, 0.66-1.20)]. A direct comparison between n-BP and etidronate (n = 340 pairs) also suggested a better survival for n-BP [paired HR, 0.47 (95%CI, (95% CI, 031-0.70)] for n-BP vs. etidronate]. CONCLUSION: Compared to no treatment, nitrogen but not non-nitrogen bisphosphonates appear to be associated with better survival.

Cross-sectional survey evaluating blood pressure control ACHIEVEment in hypertensive patients treated with multiple anti-hypertensive agents in Belgium and Luxembourg.

OBJECTIVE: This study evaluates the actual blood pressure control rate and its estimation by general practitioners, the use of single-pill or free combinations, and the attitude towards single-pill combinations in primary care. METHODS: Cross-sectional observational survey in primary care between January 2015 and September 2016 in Belgium and Luxembourg. The participating general practitioners enrolled hypertensive patients taking at least 2 antihypertensive molecules (as fixed or free associations). RESULTS: 742 general practitioners included a total of 8,006 patients, with a mean age of 66 ± 12 years. Systolic blood pressure and diastolic blood pressure were respectively 141 ± 17 mmHg and 82 ± 10 mmHg (means ± SD). These patients had a blood pressure control rate of 45%, whereas it was estimated by general practitioners to be 60%. General practitioners with 11-25 years' experience performed better than general practitioners with 36-51 years' experience in the evaluation of blood pressure control. Combinations used were free in 39%, single-pill in 34% and mixed in 27% of the patients. Patients receiving single-pill combinations were younger than those treated with free combinations (63 ± 12 vs. 68 ± 12 years, p < 0.001), with fewer comorbidities (39 vs. 55%, p < 0.001). In patients treated solely with free pill associations, 66% of patient cases, general practitioners were willing to switch to a single-pill combination. The main reasons were improved adherence (76%) and better blood pressure control (64%). CONCLUSION: In patients requiring at least two antihypertensive drugs, blood pressure control rate remains low and is overestimated by general practitioners. Free combinations remain largely used although many general practitioners seem willing to shift to single-pill combinations. Treatment simplification could improve adherence and blood pressure control rate, which has been shown to lead to reduced morbidity and mortality.

Diagnosis and management of bone fragility in diabetes: an emerging challenge.

Fragility fractures are increasingly recognized as a complication of both type 1 and type 2 diabetes, with fracture risk that increases with disease duration and poor glycemic control. Yet the identification and management of fracture risk in these patients remains challenging. This review explores the clinical characteristics of bone fragility in adults with diabetes and highlights recent studies that have evaluated bone mineral density (BMD), bone microstructure and material properties, biochemical markers, and fracture prediction algorithms (i.e., FRAX) in these patients. It further reviews the impact of diabetes drugs on bone as well as the efficacy of osteoporosis treatments in this population. We finally propose an algorithm for the identification and management of diabetic patients at increased fracture risk.

International Osteoporosis Foundation and European Calcified Tissue Society Working Group. Recommendations for the screening of adherence to oral bisphosphonates.

Adherence to oral bisphosphonates is low. A screening strategy is proposed based on the response of biochemical markers of bone turnover after 3 months of therapy. If no change is observed, the clinician should reassess the adherence to the treatment and also other potential issues with the drug. INTRODUCTION: Low adherence to oral bisphosphonates is a common problem that jeopardizes the efficacy of treatment of osteoporosis. No clear screening strategy for the assessment of compliance is widely accepted in these patients. METHODS: The International Osteoporosis Foundation and the European Calcified Tissue Society have convened a working group to propose a screening strategy to detect a lack of adherence to these drugs. The question to answer was whether the bone turnover markers (BTMs) PINP and CTX can be used to identify low adherence in patients with postmenopausal osteoporosis initiating oral bisphosphonates for osteoporosis. The findings of the TRIO study specifically address this question and were used as the basis for testing the hypothesis. RESULTS: Based on the findings of the TRIO study, specifically addressing this question, the working group recommends measuring PINP and CTX at baseline and 3 months after starting therapy to check for a decrease above the least significant change (decrease of more than 38% for PINP and 56% for CTX). Detection rate for the measurement of PINP is 84%, for CTX 87% and, if variation in at least one is considered when measuring both, the level of detection is 94.5%. CONCLUSIONS: If a significant decrease is observed, the treatment can continue, but if no decrease occurs, the clinician should reassess to identify problems with the treatment, mainly low adherence.

Salba-chia (Salvia hispanica L.) in the treatment of overweight and obese patients with type 2 diabetes: A double-blind randomized controlled trial.

BACKGROUND AND AIM: Preliminary findings indicate that consumption of Salba-chia (Salvia hispanica L.), an ancient seed, improves management of type 2 diabetes and suppresses appetite. The aim of this study was to assesse the effect of Salba-chia on body weight, visceral obesity and obesity-related risk factors in overweight and obese adults with type 2 diabetes. METHODS: A double-blind, randomized, controlled trial with two parallel groups involved 77 overweight or obese patients with type 2 diabetes (HbA1c: 6.5-8.0%; BMI: 25-40 kg/m2). Both groups followed a 6-month calorie-restricted diet; one group received 30 g/1000 kcal/day of Salba-chia, the other 36 g/1000 kcal/day of an oat bran-based control. Primary endpoint was change in body weight over 6-months. Secondary endpoints included changes in waist circumference, body composition, glycemic control, C-reactive protein, and obesity-related satiety hormones. RESULTS: At 6-months, participants on Salba-chia had lost more weight than those on control (1.9 ± 0.5 kg and 0.3 ± 0.4 kg, respectively; P = 0.020), accompanied by a greater reduction in waist circumference (3.5 ± 0.7 cm and 1.1 ± 0.7 cm, respectively; P = 0.027). C-reactive protein was reduced by 1.1 ± 0.5 mg/L (39 ± 17%) on Salba-chia, compared to 0.2 ± 0.4 mg/L (7 ± 20%) on control (P = 0.045). Plasma adiponectin on the test intervention increased by 6.5 ± 0.7%, with no change observed on control (P = 0.022). CONCLUSIONS: The results of this study, support the beneficial role of Salba-chia seeds in promoting weight loss and improvements of obesity related risk factors, while maintaining good glycemic control. Supplementation of Salba-chia may be a useful dietary addition to conventional therapy in the management of obesity in diabetes. REGISTRATION: clinicaltrials.gov identifier: NCT01403571.

The association between sclerostin and incident type 2 diabetes risk: a cohort study.

OBJECTIVE: To determine whether sclerostin is associated with fasting glucose, insulin levels, insulin resistance or increased risk of incident type 2 diabetes. BACKGROUND: Type 2 diabetic patients have a higher risk of fractures. Recent studies suggest sclerostin, a regulator of osteoblast activity, is associated with diabetes. MATERIALS AND METHODS: Sclerostin levels were obtained from 1778 individuals with no history of type 2 diabetes participating in the population-based Canadian Multicentre Osteoporosis Study (CaMos) cohort. Participants were followed until diagnosis of type 2 diabetes, death or end of the study period (31 December 2013). The relationship of sclerostin with fasting glucose, insulin levels and homoeostatic model assessment-insulin resistance (HOMA-IR) was studied in linear regression models. Cox proportional hazards models were used to determine the association of sclerostin levels and the risk of incident type 2 diabetes during a mean 7·5 years of follow-up. RESULTS: Fasting glucose, fasting insulin levels and HOMA-IR were weakly correlated with sclerostin levels (Spearman's correlation coefficient: 0·11, P < 0·05; -0·09, P < 0·05; and -0·07, P = 0·02, respectively). Multiple linear regression analyses confirmed a significant association between sclerostin and fasting insulin and HOMA-IR but no significant association with fasting glucose levels. Sclerostin levels were not found to be significantly associated with the risk of incident type 2 diabetes (HR: 1·30; 95% CI: 0·37-4·57). CONCLUSIONS: We observed an association between sclerostin levels with fasting insulin levels and HOMA-IR, but there was no clear association with type 2 diabetes risk. Further studies are needed to understand the role of sclerostin in type 2 diabetes.

Direct comparison of FRAX(R) and a simplified fracture risk assessment tool in routine clinical practice: a registry-based cohort study.

UNLABELLED: FRAX(R) incrementally improved prediction of incident major osteoporotic fractures compared with the simplified Canadian Association of Radiologists and Osteoporosis Canada (CAROC) tool. INTRODUCTION: There is debate over the value of seemingly more complex fracture prediction tools over simpler fracture prediction tools. FRAX(R) and the simplified CAROC tool are both widely used in Canada for estimating 10-year probability of major osteoporotic fractures. We compared the performance of these tools for predicting fracture outcomes. METHODS: Using a bone densitometry registry for Manitoba, Canada, we identified 34,060 individuals age ≥50 years not receiving anti-osteoporosis therapy. Fracture Risk Assessment (FRAX) and CAROC were used to classify 10-year fracture risk as low (<10 %), moderate (10-20 %) and high (>20 %). Net reclassification improvement (NRI) was used to quantify the performance of FRAX versus CAROC. RESULTS: During mean 9.8 years of follow-up, 3905 individuals sustained fractures. There were 10 (of 35 total) situations where observed fracture risk fell outside of the predicted range, and all 10 discordances favoured FRAX. NRI among incident fracture cases was not significantly changed, but there was a significant improvement in risk categorization for those who remained fracture-free (+1.7 %, P < 0.001) resulting in overall improvement (NRI overall +0.028, P < 0.001). Within nine pre-specified subgroups, there was no case of significant worsening in NRI when using FRAX instead of CAROC. In absolute terms, only 36 individuals would need to be assessed using FRAX instead of CAROC to yield an improvement in prediction (8 among individuals with prior fracture and 4 among those with prolonged glucocorticoid use). CONCLUSIONS: FRAX provides improvement in fracture risk prediction compared with the simplified CAROC tool in individuals referred for osteoporosis screening, supporting the use of FRAX as the international reference tool for fracture risk assessment.

The effect of a dietary portfolio compared to a DASH-type diet on blood pressure.

BACKGROUND AND AIM: Compared to a DASH-type diet, an intensively applied dietary portfolio reduced diastolic blood pressure at 24 weeks as a secondary outcome in a previous study. Due to the importance of strategies to reduce blood pressure, we performed an exploratory analysis pooling data from intensively and routinely applied portfolio treatments from the same study to assess the effect over time on systolic, diastolic and mean arterial pressure (MAP), and the relation to sodium (Na(+)), potassium (K(+)), and portfolio components. METHODS AND RESULTS: 241 participants with hyperlipidemia, from four academic centers across Canada were randomized and completed either a DASH-type diet (control n = 82) or a dietary portfolio that included, soy protein, viscous fibers and nuts (n = 159) for 24 weeks. Fasting measures and 7-day food records were obtained at weeks 0, 12 and 24, with 24-h urines at weeks 0 and 24. The dietary portfolio reduced systolic, diastolic and mean arterial blood pressure compared to the control by 2.1 mm Hg (95% CI, 4.2 to -0.1 mm Hg) (p = 0.056), 1.8 mm Hg (CI, 3.2 to 0.4 mm Hg) (p = 0.013) and 1.9 mm Hg (CI, 3.4 to 0.4 mm Hg) (p = 0.015), respectively. Blood pressure reductions were small at 12 weeks and only reached significance at 24 weeks. Nuts, soy and viscous fiber all related negatively to change in mean arterial pressure (ρ = -0.15 to -0.17, p ≤ 0.016) as did urinary potassium (ρ = -0.25, p = 0.001), while the Na(+)/K(+) ratio was positively associated (ρ = 0.20, p = 0.010). CONCLUSIONS: Consumption of a cholesterol-lowering dietary portfolio also decreased blood pressure by comparison with a healthy DASH-type diet. CLINICAL TRIAL REG. NO.: NCT00438425, clinicaltrials.gov.

Associations of Protein Intake and Protein Source with Bone Mineral Density and Fracture Risk: A Population-Based Cohort Study.

UNLABELLED: High dietary protein has been hypothesized to cause lower bone mineral density (BMD) and greater fracture risk. Previous results are conflicting and few studies have assessed potential differences related to differing protein sources. OBJECTIVE: To determine associations between total protein intake, and protein intake by source (dairy, non-dairy animal, plant) with BMD, BMD change, and incident osteoporotic fracture. DESIGN/SETTING: Prospective cohort study (Canadian Multicentre Osteoporosis Study). Participants/Measures: Protein intake was assessed as percent of total energy intake (TEI) at Year 2 (1997-99) using a food frequency questionnaire (N=6510). Participants were contacted annually to ascertain incident fracture. Total hip and lumbar spine BMD was measured at baseline and Year 5. Analyses were stratified by group (men 25-49 y, men 50+ y, premenopausal women 25-49 y, and postmenopausal women 50+ y) and adjusted for major confounders. Fracture analyses were limited to those 50+ y. RESULTS: Intakes of dairy protein (with adjustment for BMI) were positively associated with total hip BMD among men and women aged 50+ y, and in men aged 25-49. Among adults aged 50+ y, those with protein intakes of <12% TEI (women) and <11% TEI (men) had increased fracture risk compared to those with intakes of 15% TEI. Fracture risk did not significantly change as intake increased above 15% TEI, and was not significantly associated with protein source. CONCLUSIONS: In contrast to hypothesized risk of high protein, we found that for adults 50+ y, low protein intake (below 15% TEI) may lead to increased fracture risk. Source of protein was a determinant of BMD, but not fracture risk.

Kinetics and dynamics of cyclosporine A in three hepatic cell culture systems.

In vitro experiments have a high potential to improve current chemical safety assessment and reduce the number of animals used. However, most studies conduct hazard assessment alone, largely ignoring exposure and kinetic parameters. Therefore, in this study the kinetics of cyclosporine A (CsA) and the dynamics of CsA-induced cyclophilin B (Cyp-B) secretion were investigated in three widely used hepatic in vitro models: primary rat hepatocytes (PRH), primary human hepatocytes (PHH) and HepaRG cells. Cells were exposed daily to CsA for up to 14 days. CsA in cells and culture media was quantified by LC-MS/MS and used for pharmacokinetic modeling. Cyp-B was quantified by western blot analysis in cells and media. All cell systems took up CsA rapidly from the medium after initial exposure and all showed a time- and concentration-dependent Cyp-B cellular depletion and extracellular secretion. Only in PRH an accumulation of CsA over 14 days repeated exposure was observed. Donor-specific effects in CsA clearance were observed in the PHH model and both PHH and HepaRG cells significantly metabolized CsA, with no bioaccumulation being observed after repeated exposure. The developed kinetic models are described in detail and show that all models under-predict the in vivo hepatic clearance of CsA, but to different extents with 27-, 24- and 2-fold for PRH, PHH and HepaRG cells, respectively. This study highlights the need for more attention to kinetics in in vitro studies.

Characteristics of hyperparathyroid states in the Canadian multicentre osteoporosis study (CaMos) and relationship to skeletal markers.

CONTEXT: PTH is an essential regulator of mineral metabolism; PTH hypersecretion may result in hyperparathyroidism including normocalcaemic, primary and secondary hyperparathyroidism. OBJECTIVE: To examine the characteristics of participants with hyperparathyroid states and the relationship to bone mineral density (BMD). DESIGN AND PARTICIPANTS: A cross-sectional study of 1872 community-dwelling men and women aged 35+ years (mostly Caucasian) with available serum PTH from Year 10 Canadian Multicentre Osteoporosis Study follow-up (2005-07). PTH was determined using a second-generation chemiluminescence immunoassay. OUTCOME MEASURES: L1-L4, femoral neck and total hip BMD. RESULTS: We established a PTH reference range (2·7-10·2 pmol/l) based on healthy participants (i.e. normal serum calcium, serum 25-hydroxyvitamin D, kidney function and body mass index, who were nonusers of antiresorptives, glucocorticoids and diuretics and not diagnosed with diabetes or thyroid disease). Participants with PTH levels in the upper reference range (5·6-10·2 pmol/l), representing a prevalence of 10·7%, had lower femoral neck and total hip BMD, by 0·030 g/cm(2) [95% confidence interval: 0·009; 0·051] and 0·025 g/cm(2) (0·001; 0·049), respectively, than those with levels 2·7-5·6 pmol/l. Participants with normocalcaemic and secondary hyperparathyroidism also had lower total hip BMD than those with levels 2·7-5·6 pmol/l, and CaMos prevalences of normocalcaemic, primary and secondary hyperparathyroidism were 3·3%, 1·4% and 5·2%, respectively. CONCLUSION: We found reduced BMD in participants with accepted hyperparathyroid states but also a notable proportion of other participants that might benefit from having lower PTH levels.

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND:Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.RESULTS:During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32).

Longitudinal changes in calcium and vitamin D intakes and relationship to bone mineral density in a prospective population-based study: the Canadian Multicentre Osteoporosis Study (CaMos).

OBJECTIVES: Our objective was to study changes in calcium and vitamin D intakes over time, and their cross-sectional and longitudinal associations with bone mineral density (BMD). METHODS: We followed 9382 women and men aged ≥25 and 899 aged 16-24, for 10 and 2 years respectively. RESULTS: Calcium and vitamin D intakes increased over time in adults, but decreased in women aged 16-18. The increased intakes in adults were largely attributable to the increased use of calcium and/or vitamin D supplements. Both the percentage of supplement users and average dose among users increased over time. There was nevertheless a high prevalence of calcium and vitamin D intake below the estimated average requirement. At baseline, higher calcium and vitamin D intakes were associated with higher total hip and femoral neck BMD in young men, and cumulatively high levels of calcium and vitamin D intakes over time contributed to better BMD maintenance at lumbar spine and hip sites in adult women. CONCLUSIONS: Although total intakes, particularly of vitamin D, frequently fell below the Institute of Medicine recommendations despite an increase over time in supplement use, we found some positive associations between total calcium and vitamin D intake and bone health.

Flexibly timed once-daily dosing with degludec: a new ultra-long-acting basal insulin.

Insulin treatment in type 1 and type 2 diabetes (T1D and T2D) is highly efficacious, but in practice, non-adherence and ineffective dose titration limit its effectiveness. Barriers to more effective insulin treatment are numerous, including hypoglycaemia, fear of hypoglycaemia and concern about weight gain. The regular treatment timing needed with conventional basal insulins [neutral protamine Hagedorn (NPH) insulin and the first-generation analogues glargine and detemir] may also make adherence to these treatments problematic for many patients. Indeed, surveys indicate that the rigidity of this schedule induces some patients with T1D and T2D to omit insulin doses. Degludec is a novel, ultra-long-acting basal insulin analogue that is as effective as insulin glargine, but significantly reduces patients' risk of nocturnal hypoglycaemia. Because of its peakless, extended and highly predictable glucose-lowering effect, once-daily dosing on a flexible schedule may be feasible with degludec. Studies testing this possibility suggest that degludec tolerates day-to-day variation in dose timing while maintaining full efficacy and low risk of nocturnal hypoglycaemia. Degludec would appear to be an appropriate choice for patients being considered for a basal analogue, and it may be particularly well suited to patients with unpredictable social or work schedules, those who travel frequently and those who find rigid scheduling of their insulin injections a burden or barrier to regular treatment.

Efficacy and safety of strontium ranelate in the treatment of osteoporosis in men.

CONTEXT: Strontium ranelate reduces vertebral and nonvertebral fracture risk in postmenopausal osteoporosis. OBJECTIVE: The objective of this study was to determine the efficacy and safety of strontium ranelate in osteoporosis in men over 2 years (main analysis after 1 year). DESIGN: This was an international, unbalanced (2:1), double-blind, randomized placebo-controlled trial (MALEO [MALE Osteoporosis]). SETTING: This international study included 54 centers in 14 countries. PARTICIPANTS: PARTICIPANTS were 261 white men with primary osteoporosis. INTERVENTION: Strontium ranelate at 2 g/d (n = 174) or placebo (n = 87) was administered. MAIN OUTCOME MEASURES: Lumbar spine (L2-L4), femoral neck, and total hip bone mineral density (BMD), biochemical bone markers, and safety were measured. RESULTS: Baseline characteristics were similar in both groups in the whole population (age, 72.9 ± 6.0 years; lumbar spine BMD T-score, -2.7 ± 1.0; femoral neck BMD T-score, -2.3 ± 0.7). Men who received strontium ranelate over 2 years had greater increases in lumbar spine BMD than those who received placebo (relative change from baseline to end, 9.7% ± 7.5% vs 2.0% ± 5.5%; between-group difference estimate (SE), 7.7% (0.9%); 95% confidence interval, 5.9%-9.5%; P < .001). There were also significant between-group differences in relative changes in femoral neck BMD (P < .001) and total hip BMD (P < .001). At the end of treatment, mean levels of serum cross-linked telopeptides of type I collagen, a marker of bone resorption, were increased in both the strontium ranelate group (10.7% ± 58.0%; P = .022) and the placebo group (34.9% ± 65.8%; P < .001). The corresponding mean changes of bone alkaline phosphatase, a marker of bone formation, were 6.4% ± 28.5% (P = .005) and 1.9% ± 25.4% (P = .505), respectively. After 2 years, the blood strontium level (129 ± 66 µmol/L) was similar to that in trials of postmenopausal osteoporosis. Strontium ranelate was generally well tolerated. CONCLUSIONS: The effects of strontium ranelate on BMD in osteoporotic men were similar to those in postmenopausal osteoporotic women, supporting its use in the treatment of osteoporosis in men.

Impact of nutrition on muscle mass, strength, and performance in older adults.

Muscle strength plays an important role in determining risk for falls, which result in fractures and other injuries. While bone loss has long been recognized as an inevitable consequence of aging, sarcopenia-the gradual loss of skeletal muscle mass and strength that occurs with advancing age-has recently received increased attention. A review of the literature was undertaken to identify nutritional factors that contribute to loss of muscle mass. The role of protein, acid-base balance, vitamin D/calcium, and other minor nutrients like B vitamins was reviewed. Muscle wasting is a multifactorial process involving intrinsic and extrinsic alterations. A loss of fast twitch fibers, glycation of proteins, and insulin resistance may play an important role in the loss of muscle strength and development of sarcopenia. Protein intake plays an integral part in muscle health and an intake of 1.0-1.2 g/kg of body weight per day is probably optimal for older adults. There is a moderate [corrected] relationship between vitamin D status and muscle strength. Chronic ingestion of acid-producing diets appears to have a negative impact on muscle performance, and decreases in vitamin B12 and folic acid intake may also impair muscle function through their action on homocysteine. An adequate nutritional intake and an optimal dietary acid-base balance are important elements of any strategy to preserve muscle mass and strength during aging.