Differing Effects of Zoledronic Acid on Bone Microarchitecture and Bone Mineral Density in Men Receiving Androgen Deprivation Therapy: A Randomized Controlled Trial.

Androgen deprivation therapy (ADT) given to men with prostate cancer causes rapid and severe sex steroid deficiency, leading to increased bone remodeling and accelerated bone loss. To examine the effects of a single dose of zoledronic acid on bone microarchitecture, we conducted a 2-year randomized placebo controlled trial in 76 men, mean age (interquartile range [IQR]) 67.8 years (63.8 to 73.9) with non-metastatic prostate cancer commencing adjuvant ADT; 39 were randomized to zoledronic acid and 37 to matching placebo. Bone microarchitecture was measured using high-resolution peripheral quantitative computed tomography (HR-pQCT). Using a mixed model, mean adjusted differences (MAD; 95% confidence interval [95% CI]) between the groups are reported as the treatment effect at several time points. Over 24 months, zoledronic acid showed no appreciable treatment effect on the primary outcomes for total volumetric bone mineral density (vBMD); radius (6.7 mg HA/cm3 [-2.0 to 15.4], p = 0.21) and tibia (1.9 mg HA/cm3 [-3.3 to 7.0], p = 0.87). Similarly, there were no between-group differences in other measures of microarchitecture, with the exception of a modest effect of zoledronic acid over placebo in total cortical vBMD at the radius over 12 months (17.3 mgHA/cm3 [5.1 to 29.5]). In contrast, zoledronic acid showed a treatment effect over 24 months on areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) at all sites, including lumbar spine (0.10 g/cm2 [0.07 to 0.13]), p < 0.001), and total hip (0.04 g/cm2 [0.03 to 0.05], p < 0.001). Bone remodeling markers were initially suppressed in the treatment group then increased but remained lower relative to placebo (MADs at 24 months CTX -176 ng/L [-275 to -76], p < 0.001; P1NP -18 mg/L [-32 to -5], p < 0.001). These findings suggest that a single dose of zoledronic acid over 2 years is ineffective in preventing the unbalanced bone remodeling and severe microstructural deterioration associated with ADT therapy. © 2020 American Society for Bone and Mineral Research.

Serum 25-Hydroxyvitamin D Insufficiency in Search of a Bone Disease.

Context: Vitamin D "insufficiency" and "deficiency" are defined as serum 25-hydroxyvitamin D [25(OH)D] levels <75 and <30 nmol/L, respectively. We aimed to determine whether these values signal hypocalcemia and hypophosphatemia, secondary hyperparathyroidism, high bone remodeling, low areal bone mineral density (aBMD), microstructural deterioration, or reduced matrix mineralization density (MMD) and so suggest whether bone fragility is present. Methods: Concentrations of 25(OH)D, calcium, phosphate, creatinine, and parathyroid hormone (PTH) were measured in 11,855 participants. Serum C-terminal telopeptide of type 1 collagen, procollagen type 1 N-terminal propeptide (P1NP), aBMD, and distal radius microstructure and MMD were measured in a second subset of 150 participants. Results: A breakpoint for calcium, PTH, and alkaline phosphatase was identified at a threshold 25(OH)D level <30 nmol/L. There was no plateau beyond 75 nmol/L. In the subgroup with measurements of bone morphology, no associations were detectable between serum 25(OH)D concentration, aBMD, trabecular density, cortical porosity, or MMD. Among 1439 participants with serum 25(OH)D <30 nmol/L, 6.1% had low serum calcium, 3.4% had low serum phosphate, 6.1% had high alkaline phosphatase, and 34.2% had elevated PTH. Most participants did not have any abnormalities. Conclusion: At a 25(OH)D threshold of ≤30 nmol/L, abnormalities in biochemical features support the notion of a "deficiency" state predisposing to bone disease. However, no deleterious effects were found in participants within an insufficiency threshold of a 25(OH)D level of 30 to 75 nmol/L, which challenges the rationale justifying vitamin D supplementation in these individuals.

Dairy food supplementation may reduce malnutrition risk in institutionalised elderly.

Malnutrition in institutionalised elderly increases morbidity and care costs. Meat and dairy foods are high-quality protein sources so adequate intakes may reduce malnutrition risk. We aimed to determine whether inadequate intakes of meat and dairy foods contribute to malnutrition in institutionalised elderly. This cross-sectional study involved 215 elderly residents (70·2 % females, mean age 85·8 years) from twenty-one aged-care facilities in Melbourne, Australia. Dietary intake was assessed using observed plate waste. Food groups and serving sizes were based on the Australian Guide to Healthy Eating. Nutrient content was analysed using a computerised nutrient analysis software (Xyris). Malnutrition risk was assessed using the Mini Nutrition Assessment (MNA) tool; a score between 24 and 30 indicates normal nutritional status. Data were analysed using robust regression. Mean MNA score was 21·6 (sd 2·7). In total, 68 % of residents were malnourished or at risk of malnutrition (MNA score≤23·5). Protein intake was 87 (sd 28) % of the Australian recommended dietary intake (RDI). Consumption averaged 1 serving each of dairy foods and meat daily. Number of dairy and meat servings related to proportion of protein RDI (both P24 points). Provision of meat and dairy foods did not meet recommended levels. On the basis of current dietary intakes in aged-care residents, increasing consumption of dairy foods to the recommended four servings daily ensures protein adequacy and may reduce malnutrition risk in institutionalised elderly, and so reduce risk of comorbidities and costs associated with malnutrition.

Evidence that calcium supplements reduce fracture risk is lacking.

Credible evidence that calcium supplements reduce the risk of vertebral, nonvertebral, or hip fractures is lacking. Flaws in study design and execution such as inclusion of calcium-replete individuals, high dropout rates, and poor compliance preclude testing the hypothesis that calcium deficiency increases fracture rates or that calcium supplements reduce them. Intent-to-treat analyses of individual trials have failed to detect antifracture efficacy. Post hoc analyses of subgroups with a low calcium intake and per-protocol analyses of compliers have reported fewer fractures in the supplemented groups. However, this may be the result of confounding by violation of randomization; compliers to placebo have a lower morbidity and mortality than noncompliers. Higher hip fracture rates and cardiac mortality in patients receiving calcium supplements, as reported in some studies, may also be due to factors other than supplementation. Hypothesis testing requires that a cohort be stratified into calcium-deficient and calcium-replete groups, with each person randomized to a supplement or placebo. This design quantifies the risk of fracture attributable to calcium deficiency and any benefit that supplementation confers in the calcium-deficient and calcium-replete groups. To regard a calcium-deficient arm as unethical begs the question. Consensus statements that support the widespread use of calcium are opinion-based; they accept claims of beneficial effects despite flaws in study design, execution, and analysis; and they reject reported adverse effects because of them. Until well designed, well executed, and well analyzed studies demonstrate a net benefit in morbidity, mortality, and cost, recommendations supporting the widespread use of calcium supplementation remain belief-based and not evidence-based.

Five years treatment with strontium ranelate reduces vertebral and nonvertebral fractures and increases the number and quality of remaining life-years in women over 80 years of age.

INTRODUCTION: Longevity has resulted in a greater proportion of the population entering a time of life when increasing bone fragility and falls predispose to fractures, particularly nonvertebral fractures. Women over 80 years of age constitute 10% of the population but contribute 30% of all fractures and 60% of all nonvertebral fractures. Despite this, few studies have examined antifracture efficacy of treatments in this high-risk group and none has provided evidence for benefits beyond 3 years. MATERIALS AND METHODS: To determine whether strontium ranelate reduces the risk of vertebral and nonvertebral fractures during 5 years, we analyzed a subgroup of 1489 female patients over 80 years of age (mean 83.5+/-3.0 years) with osteoporosis from the SOTI (spinal osteoporosis therapeutic intervention) and TROPOS (treatment of peripheral osteoporosis) studies randomized to strontium ranelate 2 g/d or placebo. All received a supplement of calcium plus vitamin D. RESULTS: By intention to treat, vertebral fracture risk was reduced by 31% (relative risk, RR=0.69; 95% confidence interval, CI 0.52-0.92), nonvertebral fracture risk by 27% (RR=0.73; 95% CI 0.57-0.95), major nonvertebral fracture risk by 33% (RR=0.67; 95% CI 0.50-0.89) and hip fracture risk by 24% (RR=0.76; 95% CI 0.50-1.15, not significant). Treatment was cost-saving as it decreased cost and increased QALYs and life-years. DISCUSSION: Strontium ranelate safely produced a significant reduction in vertebral and nonvertebral fracture risk during 5 years in postmenopausal women over 80 years of age and was cost saving.

Early responsiveness of women with osteoporosis to teriparatide after therapy with alendronate or risedronate.

BACKGROUND: Anabolic responsiveness to teriparatide can be blunted or delayed in patients previously treated with alendronate. The extent of this effect is different for other antiresorptives. This study evaluated the early anabolic effects of teriparatide in postmenopausal women with osteoporosis previously treated with alendronate or risedronate. METHODS: Patients treated for at least 24 months with alendronate or risedronate discontinued their bisphosphonate and received teriparatide for 12 months. The primary endpoint was a comparison of changes from baseline in N-terminal propeptide of type 1 collagen after 3 months between prior bisphosphonate groups. We also examined changes in other bone turnover markers, bone mineral density (BMD), and relationships between early changes in bone turnover markers and 12-month areal and volumetric BMD. RESULTS: In the prior risedronate group, the N-terminal propeptide of type 1 collagen increase was significantly greater after 3 months of teriparatide than in the prior alendronate group (mean +/- se, 86.0 +/- 5.6 vs. 61.2 +/- 5.3 ng/ml, respectively; P < 0.001). Findings were similar for the other bone turnover markers. The changes in areal BMD and trabecular spine volumetric BMD were also greater in the prior risedronate group (P < 0.05). Early changes in bone turnover markers correlated with changes in trabecular spine volumetric BMD at 12 months (Spearman r = 0.45). Teriparatide was well tolerated. CONCLUSION: This nonrandomized but prospective study suggests that there may be differences in anabolic responsiveness to teriparatide as a function of the type of prior bisphosphonate exposure.

Osteoporosis and the global competition for health care resources.

Global aging superimposed on existing infectious diseases and trauma will aggravate competition for health care resources to diagnose and treat osteoporosis. Efforts to implement public health measures are needed, but the targeted approach to assessment and treatment of high-risk individuals must also be refined. Increases in the elderly population worldwide will cause a dramatic rise in osteoporotic fractures, but other age-related diseases will increase as well. Changes will be superimposed on existing public health problems (e.g., malaria, alcoholism), and these acute health care needs will take priority in some areas. Societies in most parts of the world may have to limit osteoporosis control to broad public health measures, and such efforts (e.g., calcium and vitamin D supplementation) should be supported. In these regions, clinical decision-making will generally be limited to treating patients with fractures (who presumably have already failed any public health measures in place), or in a few wealthy countries, to patients with low bone density identified by case-finding. Case-finding approaches will vary with the resources available, although unselective (mass) screening by bone densitometry is largely ineffective and unaffordable anywhere. The key to clinical decision-making on behalf of individuals will be an assessment of absolute fracture risk, and the tools needed to predict the risk of an osteoporotic fracture over the next 10 years are now being developed. These include bone density measures, but also incorporate other risk factors (e.g., fracture history, corticosteroid use), which may allow extension of fracture risk prediction to nonwhite populations and to men. Even with a universal risk prediction tool, cost-effective treatment thresholds will vary by country based on the level of fracture risk in the region and on the resources available for health care. To better compete for these resources, efforts should be made to lower the cost of osteoporosis interventions. Additionally, evidence is needed that these interventions are really effective in reducing fractures in the community.

Seasonal periodicity of serum vitamin D and parathyroid hormone, bone resorption, and fractures: the Geelong Osteoporosis Study.

UNLABELLED: In this population-based study, seasonal periodicity was seen with reduced serum vitamin D, increased serum PTH, and increased bone resorption in winter. This was associated with an increased proportion of falls resulting in fracture and an increased risk of wrist and hip fractures. INTRODUCTION: In a population of women who reside in a temperate climate and do not generally receive dietary vitamin D supplementation, we investigated whether seasonal vitamin D insufficiency is associated with increased risk of fracture. MATERIALS AND METHODS: An observational, cross-sectional, population-based study set in southeastern Australia (latitude 38-39 degrees S). Participants were drawn from a well-defined community of 27,203 women >/=55 years old: 287 randomly selected from electoral rolls, 1635 with incident fractures, and 1358 presenting to a university hospital with falls. The main outcome measures were annual periodicities of ultraviolet radiation, serum 25-hydroxyvitamin D [25(OH)D], serum parathyroid hormone (PTH), serum C-telopeptide (CTx), BMD, falls, and fractures. RESULTS: Cyclic variations in serum 25(OH)D lagged 1 month behind ultraviolet radiation, peaking in summer and dipping in winter (p < 0.001). Periodicity of serum PTH was the inverse of serum 25(OH)D, with a phase shift delay of 1 month (p = 0.004). Peak serum CTx lagged peak serum PTH by 1-2 months. In late winter, a greater proportion of falls resulted in fracture (p < 0.001). Seasonal periodicity in 439 hip and 307 wrist fractures also followed a simple harmonic model (p = 0.078 and 0.002, respectively), peaking 1.5-3 months after the trough in 25(OH)D. CONCLUSIONS: A fall in 25(OH)D in winter is accompanied by increases in (1) PTH levels, (2) bone resorption, (3) the proportion of falls resulting in fracture, and (4) the frequency of hip and wrist fracture. Whether vitamin D supplementation in winter can reduce the population burden of fractures requires further investigation.

The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis.

BACKGROUND: Osteoporotic structural damage and bone fragility result from reduced bone formation and increased bone resorption. In a phase 2 clinical trial, strontium ranelate, an orally active drug that dissociates bone remodeling by increasing bone formation and decreasing bone resorption, has been shown to reduce the risk of vertebral fractures and to increase bone mineral density. METHODS: To evaluate the efficacy of strontium ranelate in preventing vertebral fractures in a phase 3 trial, we randomly assigned 1649 postmenopausal women with osteoporosis (low bone mineral density) and at least one vertebral fracture to receive 2 g of oral strontium ranelate per day or placebo for three years. We gave calcium and vitamin D supplements to both groups before and during the study. Vertebral radiographs were obtained annually, and measurements of bone mineral density were performed every six months. RESULTS: New vertebral fractures occurred in fewer patients in the strontium ranelate group than in the placebo group, with a risk reduction of 49 percent in the first year of treatment and 41 percent during the three-year study period (relative risk, 0.59; 95 percent confidence interval, 0.48 to 0.73). Strontium ranelate increased bone mineral density at month 36 by 14.4 percent at the lumbar spine and 8.3 percent at the femoral neck (P<0.001 for both comparisons). There were no significant differences between the groups in the incidence of serious adverse events. CONCLUSIONS: Treatment of postmenopausal osteoporosis with strontium ranelate leads to early and sustained reductions in the risk of vertebral fractures.