Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and nonvertebral fractures

Dual-energy X-ray absorptiometric bone mineral density (DXA BMD) is a strong predictor of fracture risk in untreated patients. However, previous patient-level studies suggest that BMD changes explain little of the fracture risk reduction observed with osteoporosis treatment. We investigated the relevance of DXA BMD changes as a predictor for fracture risk reduction using data from the FREEDOM trial, which randomly assigned placebo or denosumab 60 mg every 6 months to 7808 women aged 60 to 90 years with a spine or total hip BMD T-score < -2.5 and not < -4.0. We took a standard approach to estimate the percent of treatment effect explained using percent changes in BMD at a single visit (months 12, 24, or 36). We also applied a novel approach using estimated percent changes in BMD from baseline at the time of fracture occurrence (time-dependent models). Denosumab significantly increased total hip BMD by 3.2%, 4.4%, and 5.0% at 12, 24, and 36 months, respectively. Denosumab decreased the risk of new vertebral fractures by 68% (p < 0.0001) and nonvertebral fracture by 20% (p = 0.01) over 36 months. Regardless of the method used, the change in total hip BMD explained a considerable proportion of the effect of denosumab in reducing new or worsening vertebral fracture risk (35% [95% confidence interval (CI): 20%-61%] and 51% [95% CI: 39%-66%] accounted for by percent change at month 36 and change in time-dependent BMD, respectively) and explained a considerable amount of the reduction in nonvertebral fracture risk (87% [95% CI: 35% - >100%] and 72% [95% CI: 24% - >100%], respectively). Previous patient-level studies may have underestimated the strength of the relationship between BMD change and the effect of treatment on fracture risk or this relationship may be unique to denosumab.     

Zoledronic acid improves bone mineral density in pediatric spinal cord injury

Spinal cord injury (SCI) is associated with rapid and sustained bone loss and increase risk of fracture. Disuse is the primary cause for bone loss, although neural and hormonal changes may also contribute via different mechanisms. Bisphosphonates are used widely to treat osteoporosis in adults and are used increasingly for primary and secondary osteoporosis in children. Current data are insufficient to recommend routine use of bisphosphonates for fracture prevention in adult patients post-SCI and there are no available data in pediatric SCI. We report a 12-year-old boy with non-traumatic SCI who was treated with six monthly zoledronic acid (0.05 mg/kg/dose) for 18 months. The patient (AA) was diagnosed with transverse myelitis at 8.1 years of age, resulting in ventilator-dependent incomplete C3 tetraplegia. Following a fragility fracture to the surgical neck of the right humerus at 9.5 years of age, he was started on zoledronic acid. Bone turnover decreased and bone densitometry data (dual-energy X-ray absorptiometry [DXA] and peripheral quantitative computed tomography [pQCT]) showed improvement in metaphyseal and diaphyseal bone mineral content (BMC), volumetric bone mineral density (vBMD), and size, after 18 months of treatment. In the growing skeleton post-SCI, zoledronic acid potentially increases vertebral and long-bone strength by preserving trabecular bone (increased BMC and vBMD) and increasing cortical vBMD and cross-sectional area (CSA).     

Distribution of bone density in the proximal femur and its association with hip fracture risk in older men: The osteoporotic fractures in men (MrOS) study

This prospective case‐cohort study aimed to map the distribution of bone density in the proximal femur and examine its association with hip fracture. We analyzed baseline quantitative computed tomography (QCT) scans in 250 men aged 65 years or older, which comprised a randomly‐selected subcohort of 210 men and 40 cases of first hip fracture during a mean follow‐up period of 5.5 years. We quantified cortical, trabecular, and integral volumetric bone mineral density (vBMD), and cortical thickness (CtTh) in four quadrants of cross‐sections along the length of the femoral neck (FN), intertrochanter (IT), and trochanter (TR). In most quadrants, vBMDs and CtTh were significantly (p < 0.05) lower in cases compared to the subcohort and these deficits were present across the entire proximal femur. To examine the association of QCT measurements with hip fracture, we merged the two quadrants in the medial and lateral aspects of the FN, IT, and TR. At most sites, QCT measurements were associated significantly (p < 0.001) with hip fracture, the hazard ratio (HR) adjusted for age, body mass index (BMI), and clinical site for a 1‐SD decrease ranged between 2.28 (95% confidence interval [CI], 1.44–3.63) to 6.91 (95% CI, 3.11–15.53). After additional adjustment for total hip (TH) areal BMD (aBMD), trabecular vBMDs at the FN, TR, and TH were still associated with hip fracture significantly (p < 0.001), the HRs ranged from 3.21 (95% CI, 1.65–6.24) for the superolateral FN to 6.20 (95% CI, 2.71–14.18) for medial TR. QCT measurements alone or in combination did not predict fracture significantly (p > 0.05) better than TH aBMD. With an area under the receiver operating characteristic curve (AUC) of 0.901 (95% CI, 0.852–0.950), the regression model combining TH aBMD, age, and trabecular vBMD predicted hip fracture significantly (p < 0.05) better than TH aBMD alone or TH aBMD plus age. These findings confirm that both cortical and trabecular bone contribute to hip fracture risk and highlight trabecular vBMD at the FN and TR as an independent risk factor. © 2012 American Society for Bone and Mineral Research.     

Post-fracture Risk Assessment: Target the Centrally Sited Fractures First! A Substudy of NoFRACT

The location of osteoporotic fragility fractures adds crucial information to post-fracture risk estimation. Triaging patients according to fracture site for secondary fracture prevention can therefore be of interest to prioritize patients considering the high imminent fracture risk. The objectives of this cross-sectional study were therefore to explore potential differences between central (vertebral, hip, proximal humerus, pelvis) and peripheral (forearm, ankle, other) fractures. This substudy of the Norwegian Capture the Fracture Initiative (NoFRACT) included 495 women and 119 men ≥50 years with fragility fractures. They had bone mineral density (BMD) of the femoral neck, total hip, and lumbar spine assessed using dual-energy X-ray absorptiometry (DXA), trabecular bone score (TBS) calculated, concomitantly vertebral fracture assessment (VFA) with semiquantitative grading of vertebral fractures (SQ1–SQ3), and a questionnaire concerning risk factors for fractures was answered. Patients with central fractures exhibited lower BMD of the femoral neck (765 versus 827 mg/cm²), total hip (800 versus 876 mg/cm²), and lumbar spine (1024 versus 1062 mg/cm²); lower mean TBS (1.24 versus 1.28); and a higher proportion of SQ1-SQ3 fractures (52.0% versus 27.7%), SQ2–SQ3 fractures (36.8% versus 13.4%), and SQ3 fractures (21.5% versus 2.2%) than patients with peripheral fractures (all p < 0.05). All analyses were adjusted for sex, age, and body mass index (BMI); and the analyses of TBS and SQ1–SQ3 fracture prevalence was additionally adjusted for BMD). In conclusion, patients with central fragility fractures revealed lower femoral neck BMD, lower TBS, and higher prevalence of vertebral fractures on VFA than the patients with peripheral fractures. This suggests that patients with central fragility fractures exhibit more severe deterioration of bone structure, translating into a higher risk of subsequent fragility fractures and therefore they should get the highest priority in secondary fracture prevention, although attention to peripheral fractures should still not be diminished. © 2019 American Society for Bone and Mineral Research. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Effects of denosumab on fracture and bone mineral density by level of kidney function

The incidences of osteoporosis and chronic kidney disease (CKD) both increase with increasing age, yet there is a paucity of data on treatments for osteoporosis in the setting of impaired kidney function. We examined the efficacy and safety of denosumab (DMAb) among subjects participating in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Study. We estimated creatinine clearance (eGFR) using Cockcroft‐Gault and classified levels of kidney function using the modified National Kidney Foundation classification of CKD. We examined incident fracture rates; changes in bone mineral density (BMD), serum calcium, and creatinine; and the incidence of adverse events after 36 months of follow‐up in subjects receiving DMAb or placebo, stratified by level of kidney function. We used a subgroup interaction term to determine if there were differences in treatment effect by eGFR. Most (93%) women were white, and the mean age was 72.3 ± 5.2 years; 73 women had an eGFR of 15 to 29 mL/min; 2817, between 30 to 59 mL/min; 4069, between 60 to 89 mL/min, and 842 had an eGFR of 90 mL/min or greater. None had stage 5 CKD. Fracture risk reduction and changes in BMD at all sites were in favor of DMAb. The test for treatment by subgroup interaction was not statistically significant, indicating that treatment efficacy did not differ by kidney function. Changes in creatinine and calcium and the incidence of adverse events were similar between groups and did not differ by level of kidney function. It is concluded that DMAb is effective at reducing fracture risk and is not associated with an increase in adverse events among patients with impaired kidney function. © 2011 American Society for Bone and Mineral Research     

Effects of zoledronate versus placebo on spine bone mineral density and microarchitecture assessed by the trabecular bone score in postmenopausal women with osteoporosis: A three‐year study

The trabecular bone score (TBS) is an index of bone microarchitectural texture calculated from anteroposterior dual‐energy X‐ray absorptiometry (DXA) scans of the lumbar spine (LS) that predicts fracture risk, independent of bone mineral density (BMD). The aim of this study was to compare the effects of yearly intravenous zoledronate (ZOL) versus placebo (PLB) on LS BMD and TBS in postmenopausal women with osteoporosis. Changes in TBS were assessed in the subset of 107 patients recruited at the Department of Osteoporosis of the University Hospital of Berne, Switzerland, who were included in the HORIZON trial. All subjects received adequate calcium and vitamin D3. In these patients randomly assigned to either ZOL (n = 54) or PLB (n = 53) for 3 years, BMD was measured by DXA and TBS assessed by TBS iNsight (v1.9) at baseline and 6, 12, 24, and 36 months after treatment initiation. Baseline characteristics (mean ± SD) were similar between groups in terms of age, 76.8 ± 5.0 years; body mass index (BMI), 24.5 ± 3.6 kg/m²; TBS, 1.178 ± 0.1 but for LS T‐score (ZOL–2.9 ± 1.5 versus PLB–2.1 ± 1.5). Changes in LS BMD were significantly greater with ZOL than with PLB at all time points (p < 0.0001 for all), reaching +9.58% versus +1.38% at month 36. Change in TBS was significantly greater with ZOL than with PLB as of month 24, reaching +1.41 versus–0.49% at month 36; p = 0.031, respectively. LS BMD and TBS were weakly correlated (r = 0.20) and there were no correlations between changes in BMD and TBS from baseline at any visit. In postmenopausal women with osteoporosis, once‐yearly intravenous ZOL therapy significantly increased LS BMD relative to PLB over 3 years and TBS as of 2 years. © 2013 American Society for Bone and Mineral Research.     

Relationship of changes in total hip bone mineral density to vertebral and nonvertebral fracture risk in women with postmenopausal osteoporosis treated with once-yearly zoledronic acid 5 mg: the HORIZON-Pivotal Fracture Trial (PFT)

Measurements of change in bone mineral density (BMD) are thought to be weak predictors of treatment effect on the reduction of fracture risk. In this study we report an alternative year-on-year approach for the estimation of treatment effect explained by BMD in which we examine the relationship between fracture risk and the most recent change in BMD. We studied 7736 postmenopausal women (ages 65 to 89 years) who were participants in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) and were randomized to either intravenous administration of zoledronic acid or placebo. The percentage of treatment effect explained by change in total hip BMD was estimated using the alternative year-on-year approach and the standard approach of looking at change over 3 years. We also studied a subset of 1132 women in whom procollagen type 1 amino-terminal propeptide (PINP) was measured at baseline and 12 months, to estimate the percentage of treatment effect explained by change in PINP. Regardless of the method used, the change in total hip BMD explained a large percentage of the effect of zoledronic acid in reducing new vertebral fracture risk (40%; 95% CI, 30% to 54%; for the 3-year analysis). The treatment effects for nonvertebral fracture were not statistically significant for the year-on-year analysis but 3-year change in BMD explained 61% (95% CI, 24% to 156%) of treatment effect. Change in PINP explained 58% (95% CI, 15% to 222%) of the effect of zoledronic acid in reducing new vertebral fracture risk. We conclude that our estimates of the percentage of treatment effect explained may be higher than in previous studies because of high compliance with zoledronic acid (due to its once-yearly intravenous administration). Previous studies may have underestimated the relationship between BMD change and the effect of treatment on fracture risk.     

Lower fracture risk in older men with higher sclerostin concentration: A prospective analysis from the MINOS study

Sclerostin is synthesized by osteocytes and inhibits bone formation. We measured serum sclerostin levels in 710 men aged 50 years and older. Bone mineral density (BMD) was measured at the lumbar spine, hip, and distal forearm. Serum sclerostin increased with age (unadjusted r = 0.30, p < 0.001). After adjustment for age, weight, and bioavailable 17β‐estradiol, serum sclerostin correlated positively with BMD (r = 0.24 to 0.35, p < 0.001) and negatively with the levels of bone turnover markers (r = ? 0.09 to ? 0.23, p < 0.05 to 0.001). During a 10‐year follow‐up, 75 men sustained fragility fractures. Fracture risk was lower in the two upper quintiles of sclerostin combined versus three lower quintiles combined (6.1 versus 13.5%, p < 0.01). We compared fracture risk in the two highest quintiles combined versus three lower quintiles combined using the Cox model adjusted for age, weight, leisure physical activity, BMD, bone width (tubular bones), prevalent fracture, prevalent falls, ischemic heart disease, and severe abdominal aortic calcification. Men with higher sclerostin concentration had lower fracture risk (adjusted for hip BMD, hazard ratio [HR] = 0.55, 95% confidence interval [CI] 0.31 to 0.96, p < 0.05). The results were similar in 47 men with major fragility fractures (adjusted for lumbar spine BMD: HR = 0.39, 95% CI 0.17 to 0.90, p < 0.05). Men who had higher sclerostin and higher BMD (two highest quintiles) had lower risk of fracture compared with men who had lower BMD and lower sclerostin levels (three lower quintiles) (HR = 0.24, 95% CI 0.10 to 0.62, p < 0.005). Circulating sclerostin was not associated with mortality rate or the incidence of major cardiovascular events. Thus, in older men, higher serum sclerostin levels are associated with lower risk of fracture, higher BMD, and lower bone turnover rate. © 2013 American Society for Bone and Mineral Research.     

Vertebral Size,Bone Density,and Strength in Men and Women Matched for Age and Areal Spine BMD

To explore the possible mechanisms underlying sex‐specific differences in skeletal fragility that may be obscured by two‐dimensional areal bone mineral density (aBMD) measures, we compared quantitative computed tomography (QCT)‐based vertebral bone measures among pairs of men and women from the Framingham Heart Study Multidetector Computed Tomography Study who were matched for age and spine aBMD. Measurements included vertebral body cross‐sectional area (CSA, cm²), trabecular volumetric BMD (Tb.vBMD, g/cm³), integral volumetric BMD (Int.vBMD, g/cm³), estimated vertebral compressive loading and strength (Newtons) at L₃, the factor‐of‐risk (load‐to‐strength ratio), and vertebral fracture prevalence. We identified 981 male‐female pairs (1:1 matching) matched on age (± 1 year) and QCT‐derived aBMD of L₃ (± 1%), with an average age of 51 years (range 34 to 81 years). Matched for aBMD and age, men had 20% larger vertebral CSA, lower Int.vBMD (–8%) and Tb.vBMD (–9%), 10% greater vertebral compressive strength, 24% greater vertebral compressive loading, and 12% greater factor‐of‐risk than women (p < 0.0001 for all), as well as higher prevalence of vertebral fracture. After adjusting for height and weight, the differences in CSA and volumetric bone mineral density (vBMD) between men and women were attenuated but remained significant, whereas compressive strength was no longer different. In conclusion, vertebral size, morphology, and density differ significantly between men and women matched for age and spine aBMD, suggesting that men and women attain the same aBMD by different mechanisms. These results provide novel information regarding sex‐specific differences in mechanisms that underlie vertebral fragility. © 2014 American Society for Bone and Mineral Research.     

Lower trabecular volumetric BMD at metaphyseal regions of weight‐bearing bones is associated with prior fracture in young girls

Understanding the etiology of skeletal fragility during growth is critical for the development of treatments and prevention strategies aimed at reducing the burden of childhood fractures. Thus we evaluated the relationship between prior fracture and bone parameters in young girls. Data from 465 girls aged 8 to 13 years from the Jump‐In: Building Better Bones study were analyzed. Bone parameters were assessed at metaphyseal and diaphyseal sites of the nondominant femur and tibia using peripheral quantitative computed tomography (pQCT). Dual‐energy X‐ray absorptiometry (DXA) was used to assess femur, tibia, lumbar spine, and total body less head bone mineral content. Binary logistic regression was used to evaluate the relationship between prior fracture and bone parameters, controlling for maturity, body mass, leg length, ethnicity, and physical activity. Associations between prior fracture and all DXA and pQCT bone parameters at diaphyseal sites were nonsignificant. In contrast, lower trabecular volumetric BMD (vBMD) at distal metaphyseal sites of the femur and tibia was significantly associated with prior fracture. After adjustment for covariates, every SD decrease in trabecular vBMD at metaphyseal sites of the distal femur and tibia was associated with 1.4 (1.1–1.9) and 1.3 (1.0–1.7) times higher fracture prevalence, respectively. Prior fracture was not associated with metaphyseal bone size (ie, periosteal circumference). In conclusion, fractures in girls are associated with lower trabecular vBMD, but not bone size, at metaphyseal sites of the femur and tibia. Lower trabecular vBMD at metaphyseal sites of long bones may be an early marker of skeletal fragility in girls. © 2011 American Society for Bone and Mineral Research.     

In vivo discrimination of hip fracture with quantitative computed tomography: Results from the prospective European Femur Fracture Study (EFFECT)

In assessing osteoporotic fractures of the proximal femur, the main objective of this in vivo case‐control study was to evaluate the performance of quantitative computed tomography (QCT) and a dedicated 3D image analysis tool [Medical Image Analysis Framework—Femur option (MIAF‐Femur)] in differentiating hip fracture and non–hip fracture subjects. One‐hundred and seven women were recruited in the study, 47 women (mean age 81.6 years) with low‐energy hip fractures and 60 female non–hip fracture control subjects (mean age 73.4 years). Bone mineral density (BMD) and geometric variables of cortical and trabecular bone in the femoral head and neck, trochanteric, and intertrochanteric regions and proximal shaft were assessed using QCT and MIAF‐Femur. Areal BMD (aBMD) was assessed using dual‐energy X‐ray absorptiometry (DXA) in 96 (37 hip fracture and 59 non–hip fracture subjects) of the 107 patients. Logistic regressions were computed to extract the best discriminates of hip fracture, and area under the receiver characteristic operating curve (AUC) was calculated. Three logistic models that discriminated the occurrence of hip fracture with QCT variables were obtained (AUC = 0.84). All three models combined one densitometric variable—a trabecular BMD (measured in the femoral head or in the trochanteric region)—and one geometric variable—a cortical thickness value (measured in the femoral neck or proximal shaft). The best discriminant using DXA variables was obtained with total femur aBMD (AUC = 0.80, p = .003). Results highlight a synergistic contribution of trabecular and cortical components in hip fracture risk and the utility of assessing QCT BMD of the femoral head for improved understanding and possible insights into prevention of hip fractures. © 2011 American Society for Bone and Mineral Research.     

Effects of bazedoxifene on bone mineral density,bone turnover,and safety in postmenopausal japanese women with osteoporosis

This randomized, double‐blind, placebo‐controlled, dose‐response late phase 2 study evaluated the efficacy and safety of bazedoxifene in postmenopausal Japanese women 85 years of age or younger with osteoporosis. Eligible subjects received daily treatment with oral doses of bazedoxifene 20 or 40 mg or placebo for 2 years. Efficacy assessments included bone mineral density (BMD) at the lumbar spine and other skeletal sites, bone turnover marker levels, lipid parameters, and incidence of new fractures. Of 429 randomized subjects, 387 were evaluable for efficacy, and 423 were included in the safety analyses (mean age, 64 years). At 2 years, the mean percent changes from baseline in lumbar spine BMD were significantly greater with bazedoxifene 20 and 40 mg (2.43% and 2.74%, respectively) than with placebo (?0.65%, p < .001 for both). Both bazedoxifene doses significantly improved BMD at the total hip, femoral neck, and greater trochanter compared with placebo (p < .001 for all). Decreases in bone turnover markers were observed with bazedoxifene 20 and 40 mg as early as 12 weeks (p < .05 for all) and were sustained throughout the study. Total and low‐density lipoprotein cholesterol levels were significantly decreased from baseline with both bazedoxifene doses compared with placebo (p < .05 for all). Incidences of new vertebral and nonvertebral fractures were similar among the bazedoxifene and placebo groups. Overall, the incidence of adverse events with bazedoxifene 20 and 40 mg was similar to that with placebo. Bazedoxifene significantly improved BMD, reduced bone turnover, and was well tolerated in postmenopausal Japanese women with osteoporosis. © 2011 American Society for Bone and Mineral Research.     

Long‐term cadmium exposure and the association with bone mineral density and fractures in a population‐based study among women

All people are exposed to cadmium (Cd) via food; smokers are additionally exposed. High Cd exposure is associated with severe bone damage, but the public health impact in relation to osteoporosis and fractures at low environmental exposure remains to be clarified. Within the population‐based Swedish Mammography Cohort, we assessed urinary Cd [U‐Cd, µg/g of creatinine (cr)] as a marker of lifetime exposure and bone mineral density (BMD) by dual‐energy X‐ray absorptiometry (DXA) among 2688 women. Register‐based information on fractures was retrieved from 1997 to 2009. Associations were evaluated by multivariable regression analyses. In linear regression, U‐Cd was inversely associated with BMD at the total body (p < .001), femoral neck (p = .025), total hip (p = .004), lumbar spine (p = .088), and volumetric femoral neck (p = .013). In comparison with women with U‐Cd < 0.50 µg/g of cr, those with U‐Cd ≥ 0.75 µg/g of cr had odds ratios (ORs) of 2.45 [95% confidence interval (CI) 1.51–3.97] and 1.97 (95% CI 1.24–3.14) for osteoporosis at the femoral neck and lumbar spine, respectively. Among never‐smokers, the corresponding ORs were 3.47 (95% CI 1.46–8.23) and 3.26 (95% CI 1.44–7.38). For any first fracture (n = 395), the OR was 1.16 (95% CI 0.89–1.50) comparing U‐Cd ≥ 0.50 µg/g of cr with lower levels. Among never‐smokers, the ORs (95% CIs) were 2.03 (1.33–3.09) for any first fracture, 2.06 (1.28–3.32) for first osteoporotic fracture, 2.18 (1.20–3.94) for first distal forearm fracture, and 1.89 (1.25–2.85) for multiple incident fractures. U‐Cd at low environmental exposure from food in a general population of women showed modest but significant association with both BMD and fractures, especially in never‐smokers, indicating a larger concern than previously known. © 2011 American Society for Bone and Mineral Research.     

Bone mineral content and density of the lumbar spine of infants and toddlers: Influence of age,sex, race,growth, and human milk feeding

Little is known about factors that affect bone mass and density of infants and toddlers and the means to assess their bone health owing to challenges in studying this population. The objectives of this study were to describe age, sex, race, growth, and human milk feeding effects on bone mineral content (BMC) and areal density (aBMD) of the lumbar spine, and determine precision of BMC and aBMD measurements. We conducted a cross‐sectional study of 307 healthy participants (63 black), ages 1 to 36 months. BMC and aBMD of the lumbar spine were measured by dual‐energy X‐ray absorptiometry. Duplicate scans were obtained on 76 participants for precision determination. Age‐specific Z‐scores for aBMD, weight, and length (BMDZ, WAZ, LAZ) were calculated. Information on human milk feeding duration was ascertained by questionnaire. Between ages 1 and 36 months, lumbar spine BMC increased about fivefold and aBMD increased twofold (p < 0.0001). BMC was greater (5.8%) in males than in females (p = 0.001), but there was no difference in aBMD (p = 0.37). There was no difference in BMC or aBMD between whites and blacks (p ≥ 0.16). WAZ and LAZ were positively associated with BMDZ (r = 0.34 and 0.24, p < 0.001). Duration of human milk feeding was negatively associated with BMDZ in infants <12 months of age (r = ?0.42, p < 0.001). Precision of BMC and aBMD measurements was good, 2.20% and 1.84%, respectively. Dramatic increases in BMC and aBMD of the lumbar spine occur in the first 36 months of life. We provide age‐specific values for aBMD of healthy infants and toddlers that can be used to evaluate bone deficits. Future studies are needed to identify the age when sex and race differences in aBMD occur, and how best to account for delayed or accelerated growth in the context of bone health assessment of infants and toddlers. © 2013 American Society for Bone and Mineral Research     

Breastfeeding protects against hip fracture in postmenopausal women: The Tromsø study

Despite reported bone loss during pregnancy and lactation, no study has shown deleterious long‐term effects of parity or breastfeeding. Studies have shown higher bone mineral density and reduced risk for fracture in parous than in nulliparous women or no effect of parity and breastfeeding, so long‐term effects are uncertain. We studied the effect of parity and breastfeeding on risk for hip, wrist and non‐vertebral fragility fractures (hip, wrist, or proximal humerus) in 4681 postmenopausal women aged 50 to 94 years in the Tromsø Study from 1994–95 to 2010, using Cox's proportional hazard models. During 51 906 person‐years, and a median of 14.5 years follow‐up, 442, 621, and 1105 of 4681 women suffered incident hip, wrist, and fragility fractures, and the fracture rates were 7.8, 11.4, and 21.3 per 1000 person‐years, respectively. The risk for hip, wrist, and fragility fracture did not differ between parous (n = 4230, 90.4%) and nulliparous women (n = 451, 9.6%). Compared with women who did not breast‐feed after birth (n = 184, 4.9%), those who breastfed (n = 3564, 95.1%) had 50% lower risk for hip fracture (HR 0.50; 95% CI 0.32 to 0.78), and 27% lower risk for fragility fracture (HR 0.73; 95% CI 0.54 to 0.99), but similar risk for wrist fracture, after adjustment for age, BMI, height, physical activity, smoking, a history of diabetes, previous fracture of hip or wrist, use of hormone replacement therapy, and length of education. Each 10 months longer total duration of breastfeeding reduced the age‐adjusted risk for hip fracture by 12% (HR 0.88; 95% CI 0.78 to 0.99, p for trend = 0.03) before, and marginally after, adjustment for BMI and other covariates (HR 0.91; 95% CI 0.80 to 1.04). In conclusion, this data indicates that pregnancy and breastfeeding has no long‐term deleterious effect on bone fragility and fractures, and that breastfeeding may contribute to a reduced risk for hip fracture after menopause. © 2011 American Society for Bone and Mineral Research     

Postmenopausal osteoporosis treatment with antiresorptives: effects of discontinuation or long-term continuation on bone turnover and fracture risk--a perspective

Osteoporosis may be a lifelong condition. Robust data regarding the efficacy and safety of both long-term osteoporosis therapy and therapy discontinuation are therefore important. A paucity of clinical trial data regarding the long-term antifracture efficacy of osteoporosis therapies necessitates the use of surrogate endpoints in discussions surrounding long-term use and/or discontinuation. Long-term treatment (beyond 3-4 years) may produce further increases in bone mineral density (BMD) or BMD stability, depending on the specific treatment and the skeletal site. Bisphosphonates, when discontinued, are associated with a prolonged reduction in bone turnover markers (BTMs), with a very gradual increase to pretreatment levels within 3 to 60 months of treatment cessation, depending on the bisphosphonate used and the prior duration of therapy. In contrast, with nonbisphosphonate antiresorptive agents, such as estrogen and denosumab, BTMs rebound to above pretreatment values within months of discontinuation. The pattern of BTM change is generally mirrored by a more or less rapid decrease in BMD. Although the prolonged effect of some bisphosphonates on BTMs and BMD may contribute to residual benefit on bone strength, it may also raise safety concerns. Adequately powered postdiscontinuation fracture studies and conclusive evidence on maintenance or loss of fracture benefit is lacking for bisphosphonates. Similarly, the effects of rapid reversal of bone turnover upon discontinuation of denosumab on fracture risk remain unknown. Ideally, studies evaluating the effects of long-term treatment and treatment discontinuation should be designed to provide head-to-head "offset" data between bisphosphonates and nonbisphosphonate antiresorptive agents. In the absence of this, a clinical recommendation for physicians may be to periodically assess the benefits/risks of continuation versus discontinuation versus alternative management strategies.     

Serum uric acid is associated with bone health in older men: A cross‐sectional population‐based study

Serum uric acid (UA) is a strong endogenous antioxidant. Since oxidative stress has been linked to osteoporosis, we examined the association between serum UA levels and bone mineral density (BMD), prevalent vertebral and nonvertebral fractures, and laboratory measures such as calcitropic hormones and bone turnover marker levels. This cross‐sectional analysis consisted of 1705 community‐dwelling men aged 70 years or over who participated in the baseline part of the Concord Health and Ageing in Men Project (CHAMP), a population‐based study of older men in Sydney, Australia. BMD at all sites was significantly higher among men with serum UA levels above the group median than among men with UA levels below the median. In multiple regression analyses adjusted for potential confounders, serum UA remained associated with BMD at all sites (β = 0.12 to 0.14, p < .001), serum calcium (β = 0.11, p = .001), parathyroid hormone (β = 0.09, p = .002), 25‐hydroxyvitamin D (β = 0.09, p = .005), and was negatively associated with urinary excretion amino‐terminal cross‐linked telopeptide of type 1 collagen (β = –0.09, p = .006). Overall, serum UA accounted for 1.0% to 1.44% of the variances in BMD (R² = 0.10 to 0.22). In multiple logistic regression analyses, above‐median serum UA levels were associated with a lower prevalence of osteoporosis at the femoral neck [odds ratio (OR) = 0.42, 95% confidence interval (CI) 0.22–0.81, p = .010) and lumbar spine (OR = 0.44, 95% CI 0.23–0.86, p = .016) and a lower prevalence of vertebral (OR = 0.62, 95% CI 0.43–0.91, p = .015) and nonvertebral (OR = 0.51, 95% CI 0.29–0.89, p = .018) fractures. In conclusion, higher serum UA levels are associated with higher BMD at all skeletal sites and with a lower prevalence of vertebral and nonvertebral fractures in older men. © 2011 American Society for Bone and Mineral Research.     

Teriparatide increases bone mineral density in a man with osteoporosis pseudoglioma

Osteoporosis Pseudoglioma (OPPG) is characterized by severe juvenile-onset osteoporosis and ocular abnormalities. It is caused by one of several inactivating mutations in LRP5, a gene importantly involved in bone formation. The objective of this study was to evaluate the efficacy of teriparatide in a young man with OPPG. The subject of this case report is a 19-year-old man with congenital blindness and low trauma fractures because of OPPG. A 2-year course of teriparatide, 20 μg/day, was initiated after a 6-year course of intravenous pamidronate infusions, the latter 3 years of which had minimal effects on bone mineral density (BMD). Measurements in serum were made of C-terminal telopeptide of type I collagen (CTX), N-terminal propeptide of type I collagen (P1NP), total and ionized calcium, phosphate, uric acid, complete blood count, and renal and liver function tests. Urinary calcium/creatinine ratio was determined. BMD was measured by DXA yearly. BMD increased by 9.7% in lumbar spine and 10.2% in right femur hip. CTX rose early, peaking in month 3, followed by an increase in P1NP, peaking in month 9. Both indices returned to baseline by month 24. The increase in CTX followed by P1NP is an unusual time course when teriparatide is used to treat osteoporosis but may be typical of low bone turnover states. There were no adverse events. In a patient with OPPG, teriparatide markedly increased BMD in the lumbar spine and femur hip.     

Absolute fracture risk assessment using lumbar spine and femoral neck bone density measurements: Derivation and validation of a hybrid system

The World Health Organization (WHO) Fracture Risk Assessment Tool (FRAX) computes 10‐year probability of major osteoporotic fracture from multiple risk factors, including femoral neck (FN) T‐scores. Lumbar spine (LS) measurements are not currently part of the FRAX formulation but are used widely in clinical practice, and this creates confusion when there is spine‐hip discordance. Our objective was to develop a hybrid 10‐year absolute fracture risk assessment system in which nonvertebral (NV) fracture risk was assessed from the FN and clinical vertebral (V) fracture risk was assessed from the LS. We identified 37,032 women age 45 years and older undergoing baseline FN and LS dual‐energy X‐ray absorptiometry (DXA; 1990–2005) from a population database that contains all clinical DXA results for the Province of Manitoba, Canada. Results were linked to longitudinal health service records for physician billings and hospitalizations to identify nontrauma vertebral and nonvertebral fracture codes after bone mineral density (BMD) testing. The population was randomly divided into equal‐sized derivation and validation cohorts. Using the derivation cohort, three fracture risk prediction systems were created from Cox proportional hazards models (adjusted for age and multiple FRAX risk factors): FN to predict combined all fractures, FN to predict nonvertebral fractures, and LS to predict vertebral (without nonvertebral) fractures. The hybrid system was the sum of nonvertebral risk from the FN model and vertebral risk from the LS model. The FN and hybrid systems were both strongly predictive of overall fracture risk (p < .001). In the validation cohort, ROC analysis showed marginally better performance of the hybrid system versus the FN system for overall fracture prediction (p = .24) and significantly better performance for vertebral fracture prediction (p < .001). In a discordance subgroup with FN and LS T‐score differences greater than 1 SD, there was a significant improvement in overall fracture prediction with the hybrid method (p = .025). Risk reclassification under the hybrid system showed better alignment with observed fracture risk, with 6.4% of the women reclassified to a different risk category. In conclusion, a hybrid 10‐year absolute fracture risk assessment system based on combining FN and LS information is feasible. The improvement in fracture risk prediction is small but supports clinical interest in a system that integrates LS in fracture risk assessment. © 2011 American Society for Bone and Mineral Research.