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1.  Variants of the Serotonin Transporter Gene, Selective Serotonin Reuptake Inhibitors, and Bone Mineral Density in Risperidone-Treated Boys: A Reanalysis of Data From a Cross-Sectional Study With Emphasis on Pharmacogenetics 
The Journal of clinical psychiatry  2011;72(12):1685-1690.
Selective serotonin reuptake inhibitors (SSRIs) may reduce bone mineral density (BMD). Here, we investigate whether variants of the serotonin transporter-linked polymorphic region (5-HTTLPR) of the serotonin transporter gene moderate this association in boys.
Between November 2005 and August 2009, medically healthy boys, aged 7 to 17 years, were enrolled in a cross-sectional study exploring the effect of risperidone-induced hyperprolactinemia on BMD. Volumetric BMD of the ultradistal radius was measured using peripheral quantitative computed tomography, and areal BMD of the lumbar spine was estimated using dual energy x-ray absorptiometry. Multiple linear regression analysis tested whether the 5-HTTLPR genotypes interacted with SSRI treatment status to affect BMD, adjusting for relevant confounders. Participant enrollment was conducted at the University of Iowa, Iowa City.
Of 108 boys (mean ± SD age = 11.7 ± 2.8 years), with DSM-IV clinical diagnoses based on chart review, 52% (n = 56) had been taking an SSRI for a median duration of 2.8 years. After adjusting for pubertal development, anthropometric measures, physical activity, calcium intake, and prolactin concentration, there was a significant 5-HTTLPR genotype × SSRI treatment interaction effect on total lumbar spine BMD z score (P < .05) in non-Hispanic whites. The interaction effect on BMD at the ultradistal radius failed to reach statistical significance. Among LS genotype carriers, those treated with SSRIs had lower lumbar BMD z score and trabecular BMD at the radius compared to those not treated (P < .02 and P < .008, respectively).
These findings add to the growing evidence implicating the serotonin system in bone metabolism. They suggest the potential use of 5-HTTLPR genotypes to guide the safer long-term prescribing of SSRIs in youths. However, prospective confirmation in a controlled matched population is warranted.
PMCID: PMC3653135  PMID: 22244026
2.  Relation of Serum Serotonin Levels to Bone Density and Structural Parameters in Women 
Recent studies have demonstrated an important role for circulating serotonin in regulating bone mass in rodents. In addition, patients treated with selective serotonin reuptake inhibitors (SSRIs) have reduced areal bone mineral density (aBMD). However, the potential physiologic role of serotonin in regulating bone mass in humans remains unclear. Thus we measured serum serotonin levels in a population-based sample of 275 women and related these to total-body and spine aBMD assessed by dual-energy X-ray absorptiometry, femur neck total and trabecular volumetric BMD (vBMD) and vertebral trabecular vBMD assessed by quantitative computed tomography (QCT), and bone microstructural parameters at the distal radius assessed by high-resolution peripheral QCT (HRpQCT). Serotonin levels were inversely associated with body and spine aBMD (age-adjusted R = −0.17 and −0.16, P < .01, respectively) and with femur neck total and trabecular vBMD (age-adjusted R = −0.17 and −0.25, P < .01 and < .001, respectively) but not lumbar spine vBMD. Bone volume/tissue volume, trabecular number, and trabecular thickness at the radius were inversely associated with serotonin levels (age-adjusted R = −0.16, −0.16, and −0.14, P < .05, respectively). Serotonin levels also were inversely associated with body mass index (BMI; age-adjusted R = −0.23, P < .001). Multivariable models showed that serotonin levels remained significant negative predictors of femur neck total and trabecular vBMD, as well as trabecular thickness at the radius, after adjusting for age and BMI. Collectively, our data provide support for a physiologic role for circulating serotonin in regulating bone mass in humans. © 2010 American Society for Bone and Mineral Research
PMCID: PMC3153390  PMID: 19594297
serotonin; bone density; bone structure; SSRI; osteoporosis
3.  Fracture risk in children with a forearm injury is associated with volumetric bone density and cortical area (by peripheral QCT) and areal bone density (by DXA) 
Osteoporosis International  2010;22(2):607-616.
Children who sustain a forearm fracture when injured have lower bone density throughout their skeleton, and have a smaller cortical area and a lower strength index in their radius. Odds ratios per SD decrease in bone characteristics measured by peripheral quantitative computed tomography (pQCT) and dual-energy X-ray absorptiometry (DXA) were similar (1.28 to 1.41).
Forearm fractures are common in children. Bone strength is affected by bone mineral density (BMD) and bone geometry, including cross-sectional dimensions and distribution of mineral. Our objective was to identify bone characteristics that differed between children who sustained a forearm fracture compared to those who did not fracture when injured.
Children (5–16 years) with a forearm fracture (cases, n=224) and injured controls without fracture (n=200) were enrolled 28±8 days following injury. Peripheral QCT scans of the radius (4% and 20% sites) were obtained to measure volumetric BMD (vBMD) of total, trabecular and cortical bone compartments, and bone geometry (area, cortical thickness, and strength strain index [SSI]). DXA scans (forearm, spine, and hip) were obtained to measure areal BMD (aBMD) and bone area. Receiver operating characteristic (ROC) analyses were used to assess screening performance of bone measurements.
At the 4% pQCT site, total vBMD, but not trabecular vBMD or bone area, was lower (−3.4%; p= 0.02) in cases than controls. At the 20% site, cases had lower cortical vBMD (−0.9%), cortical area (−2.8%), and SSI (−4.6%) (p<0.05). aBMD, but not bone area, at the 1/3 radius, spine, and hip were 2.7–3.3% lower for cases (p< 0.01). Odds ratios per 1 SD decrease in bone measures (1.28–1.41) and areas under the ROC curves (0.56–0.59) were similar for all bone measures.
Low vBMD, aBMD, cortical area, and SSI of the distal radius were associated with an increased fracture risk. Interventions to increase these characteristics are needed to help reduce forearm fracture occurrence.
PMCID: PMC3298088  PMID: 20571770
Bone densitometry; Epidemiology; Fracture; Orthopedics; Pediatrics; QCT
4.  Bone microarchitecture in ankylosing spondylitis and the association with bone mineral density, fractures, and syndesmophytes 
Arthritis Research & Therapy  2013;15(6):R179.
Osteoporosis of the axial skeleton is a known complication of ankylosing spondylitis (AS), but bone loss affecting the peripheral skeleton is less studied. This study on volumetric bone mineral density (vBMD) and bone microarchitecture in AS was conducted to compare peripheral vBMD in AS patients with that in healthy controls, to study vBMD in axial compared with peripheral bone, and to explore the relation between vertebral fractures, spinal osteoproliferation, and peripheral bone microarchitecture and density.
High-resolution peripheral quantitative computed tomography (HRpQCT) of ultradistal radius and tibia and QCT and dual-energy x-ray absorptiometry (DXA) of lumbar spine were performed in 69 male AS patients (NY criteria). Spinal radiographs were assessed for vertebral fractures and syndesmophyte formation (mSASSS). The HRpQCT measurements were compared with the measurements of healthy controls.
The AS patients had lower cortical vBMD in radius (P = 0.004) and lower trabecular vBMD in tibia (P = 0.033), than did the controls. Strong correlations were found between trabecular vBMD in lumbar spine, radius (rS = 0.762; P < 0.001), and tibia (rS = 0.712; P < 0.001).
When compared with age-matched AS controls, patients with vertebral fractures had lower lumbar cortical vBMD (-22%; P = 0.019), lower cortical cross-sectional area in radius (-28.3%; P = 0.001) and tibia (-24.0%; P = 0.013), and thinner cortical bone in radius (-28.3%; P = 0.001) and tibia (-26.9%; P = 0.016).
mSASSS correlated negatively with trabecular vBMD in lumbar spine (rS = -0.620; P < 0.001), radius (rS = -0.400; p = 0.001) and tibia (rS = -0.475; p < 0.001) and also with trabecular thickness in radius (rS = -0.528; P < 0.001) and tibia (rS = -0.488; P < 0.001).
Adjusted for age, syndesmophytes were significantly associated with decreasing trabecular vBMD, but increasing cortical vBMD in lumbar spine, but not with increasing cortical thickness or density in peripheral bone. Estimated lumbar vBMD by DXA correlated with trabecular vBMD measured by QCT (rS = 0.636; P < 0.001).
Lumbar osteoporosis, syndesmophytes, and vertebral fractures were associated with both lower vBMD and deteriorated microarchitecture in peripheral bone. The results indicate that trabecular bone loss is general, whereas osteoproliferation is local in AS.
PMCID: PMC3978766  PMID: 24517240
5.  Increased bone mineral density is associated with breastfeeding history in premenopausal Spanish women 
During lactation abundant calcium is lost from the mother as a result of the amount of breast milk produced. Lactation leads to transient fragility, with some women experiencing even fragility fractures, but nearly all of these women subsequently undergo a large increase in bone mineral density (BMD), confirming that the BMD must have declined during lactation but it increases after weaning. We have retrospectively examined the relationship between the duration of breastfeeding and bone properties in Spanish premenopausal healthy women, to identify the site-specific changes in BMD.
Material and methods
Four hundred and thirty-three premenopausal healthy women, 295 with a mean of 7.82 ±6.68 months of exclusive breastfeeding and 138 control women, were studied. We examined total, trabecular and cortical volumetric BMD (mg/mm3) at the distal radius using peripheral quantitative computed tomography. Areal BMD (g/cm2) was measured using dual energy X-ray absorptiometry at the femoral neck, lumbar spine, trochanter and Ward's triangle. Phalangeal bone ultrasound was measured by amplitude-dependent speed of sound.
Areal BMD analysis at L2–L4 revealed significant intergroup differences (p < 0.05). There were significant intergroup differences in the volumetric BMD in both total and cortical bone (p < 0.05). The observed BMD of breast-feeders was higher than the BMD in non-breast-feeding women. Additionally, the lactation subgroup analysis revealed significant differences in the areal BMD at trochanter and L2–L4 (p < 0.05) and in the cortical volumetric BMD (p < 0.05).
This study adds to the growing evidence that breastfeeding has no deleterious effects and may confer an additional advantage for BMD in premenopausal women.
PMCID: PMC3776181  PMID: 24049532
lactation; dual-energy X-ray absorptiometry; bone mass; ultrasonography
6.  Evaluation of Trabecular Micro-Architecture in Non-Osteoporotic Post-Menopausal Women With and Without Fracture 
Journal of Bone and Mineral Research  2012;27(7):1494-1500.
To compare microscopic magnetic resonance imaging (μMRI) parameters of trabecular micro-architecture between postmenopausal women with and without fracture who have normal or osteopenic bone mineral density (BMD) on dual-energy x-ray absorptiometry (DXA).
The study included 36 post-menopausal Caucasian women 50 years of age and older with normal or osteopenic BMD (T-scores better than −2.5 at the lumbar spine, proximal femur, and one-third radius on DXA). Eighteen women had a history of low-energy fracture, while 18 women had no history of fracture and served as an age, race, and ultra-distal radius BMD-matched control group. A three-dimensional fast large-angle spin-echo (FLASE) sequence with 137 μm × 137 μm × 400 μm resolution was performed through the non-dominant wrist of all 36 women using the same 1.5T scanner. The high resolution images were used to measure trabecular bone volume fraction, trabecular thickness, surface-to-curve ratio, and erosion index. Wilcoxon signed rank tests were used to compare differences in BMD and μMRI parameters between post-menopausal women with and without fracture.
Post-menopausal women with fracture had significantly lower (p<0.05) trabecular bone volume fraction and surface-to-curve ratio and significantly higher (p<0.05) erosion index than post-menopausal women without fracture. There was no significant difference between post-menopausal women with and without fracture in trabecular thickness (p=0.80) and BMD of the spine (p=0.21), proximal femur (p=0.19), one-third radius (p=0.47), and ultra-distal radius (p=0.90).
Post-menopausal women with normal or osteopenic BMD who had a history of low energy fracture had significantly different (p<0.05) μMRI parameters than an age, race, and ultra-distal radius BMD-matched control group of postmenopausal women with no history of fracture. Our study suggests that μMRI can be used to identify individuals without a DXA-based diagnosis of osteoporosis who have impaired trabecular micro-architecture and thus a heretofore-unappreciated elevated fracture risk.
PMCID: PMC3377771  PMID: 22407970
Osteoporosis; Trabecular Micro-Architecture; Magnetic Resonance Imaging; Fracture
7.  Bone Density, Geometry, Microstructure and Stiffness: Relationships Between Peripheral and Central Skeletal Sites Assessed by DXA, HR-pQCT, and cQCT in Premenopausal Women 
High-resolution peripheral quantitative computed tomography (HR-pQCT) is a new in vivo imaging technique for assessing three-dimensional microstructure of cortical and trabecular bone at the distal radius and tibia. No studies have investigated the extent to which measurements of the peripheral skeleton by HR-pQCT reflect those of the spine and hip, where the most serious fractures occur. To address this research question, we performed dual energy absorptiometry (DXA), central QCT (cQCT), HR-pQCT, and image-based finite element analyses in 69 premenopausal women to evaluate relationships among cortical and trabecular bone density, geometry, microstructure, and stiffness of the lumbar spine, proximal femur, distal radius and distal tibia. Significant correlations were found between stiffness of the two peripheral sites (r=0.86), two central sites (r=0.49), and between peripheral and central skeletal sites (r=0.56-0.70). These associations were partially explained by significant correlations in areal BMD (aBMD), volumetric BMD (vBMD), and cross-sectional area (CSA) between the multiple skeletal sites. For prediction of proximal femoral stiffness, vBMD (r=0.75) and stiffness (r=0.69) of the distal tibia by HR-pQCT were comparable to direct measurements of the proximal femur: aBMD of hip by DXA (r=0.70) and vBMD of hip by cQCT (r=0.64). For prediction of vertebral stiffness, trabecular vBMD (r=0.58) and stiffness (r=0.70) of distal radius by HR-pQCT were comparable to direct measurements of lumbar spine: aBMD by DXA (r=0.78) and vBMD by cQCT (r=0.67). Our results suggest that bone density, microstructural and mechanical properties measured by HR-pQCT of the distal radius and tibia reflect mechanical competence of the central skeleton.
PMCID: PMC3128822  PMID: 20499344
high-resolution peripheral quantitative computed tomography; finite element analysis; lumbar spine; proximal femur; distal radius; distal tibia
8.  Early decrements in bone density after completion of neoadjuvant chemotherapy in pediatric bone sarcoma patients 
Bone mineral density (BMD) accrual during childhood and adolescence is important for attaining peak bone mass. BMD decrements have been reported in survivors of childhood bone sarcomas. However, little is known about the onset and development of bone loss during cancer treatment. The objective of this cross-sectional study was to evaluate BMD in newly diagnosed Ewing's and osteosarcoma patients by means of dual-energy x-ray absorptiometry (DXA) after completion of neoadjuvant chemotherapy.
DXA measurements of the lumbar spine (L2-4), both femora and calcanei were performed perioperatively in 46 children and adolescents (mean age: 14.3 years, range: 8.6-21.5 years). Mean Z-scores, areal BMD (g/cm2), calculated volumetric BMD (g/cm3) and bone mineral content (BMC, g) were determined.
Lumbar spine mean Z-score was -0.14 (95% CI: -0.46 to 0.18), areal BMD was 1.016 g/cm2 (95% CI: 0.950 to 1.082) and volumetric BMD was 0.330 g/cm3 (95% CI: 0.314 to 0.347) which is comparable to healthy peers. For patients with a lower extremity tumor (n = 36), the difference between the affected and non-affected femoral neck was 12.1% (95% CI: -16.3 to -7.9) in areal BMD. The reduction of BMD was more pronounced in the calcaneus with a difference between the affected and contralateral side of 21.7% (95% CI: -29.3 to -14.0) for areal BMD. Furthermore, significant correlations for femoral and calcaneal DXA measurements were found with Spearman-rho coefficients ranging from ρ = 0.55 to ρ = 0.80.
The tumor disease located in the lower extremity in combination with offloading recommendations induced diminished BMD values, indicating local osteopenia conditions. However, the results revealed no significant decrements of lumbar spine BMD in pediatric sarcoma patients after completion of neoadjuvant chemotherapy. Nevertheless, it has to be taken into account that bone tumor patients may experience BMD decrements or secondary osteoporosis in later life. Furthermore, the peripheral assessment of BMD in the calcaneus via DXA is a feasible approach to quantify bone loss in the lower extremity in bone sarcoma patients and may serve as an alternative procedure, when the established assessment of femoral BMD is not practicable due to endoprosthetic replacements.
PMCID: PMC3022904  PMID: 21190557
9.  Trabecular bone deficits among Vietnamese immigrants 
Compared to white women, lower areal bone mineral density (aBMD) in middle-aged Vietnamese immigrants is due to reduced trabecular volumetric bone mineral density (vBMD), which in turn is associated with greater trabecular separation along with lower estrogen levels.
The epidemiology of osteoporosis in Asian populations is still poorly known, but we previously found a deficit in lumbar spine aBMD among postmenopausal Southeast Asian women, compared to white women, that persisted after correction for bone size. This issue was revisited using more sophisticated imaging techniques.
Twenty Vietnamese immigrants (age, 44–79 years) were compared to 162 same-aged white women with respect to aBMD at the hip, spine and wrist, vBMD at the hip and spine by quantitative computed tomography and vBMD and bone microstructure at the ultradistal radius by high-resolution pQCT. Bone turnover and sex steroid levels were assessed in a subset (20 Vietnamese and 40 white women).
The aBMD was lower at all sites among the Vietnamese women, but femoral neck vBMD did not differ from middle-aged white women. Significant differences in lumbar spine and ultradistal radius vBMD in the Vietnamese immigrants were due to lower trabecular vBMD, which was associated with increased trabecular separation. Bone resorption was elevated and bone formation depressed among the Vietnamese immigrants, although trends were not statistically significant. Serum estradiol was positively associated with trabecular vBMD in the Vietnamese women, but their estrogen levels were dramatically lower compared to white women.
Although reported discrepancies in aBMD among Asian women are mainly an artifact of smaller bone size, we identified a specific deficit in the trabecular bone among a sample of Vietnamese immigrants that may be related to low estrogen levels and which needs further study.
PMCID: PMC3093661  PMID: 20658128
Bone mineral density; Bone structure; Bone turnover; Ethnic group; Southeast Asians
10.  Correlates of Trabecular and Cortical Volumetric Bone Mineral Density (vBMD) at the Femoral Neck and Lumbar Spine: The Osteoporotic Fractures in Men Study (MrOS) 
The objective of this cross-sectional analysis was to examine the correlates of trabecular and cortical volumetric bone mineral density (vBMD) in 3670 community dwelling men, mean age 73.6±5.9 years.
Materials and Methods
vBMD was measured by quantitative computed tomography (QCT) and areal BMD, by DXA. Demographic, history and lifestyle information was obtained by interview and height, weight, and neuromuscular function by examination. To express the strength of the associations, percent differences (95% CI) were calculated from multivariable linear regression models using the formula 100 (beta*unit/mean BMD). Units were chosen to approximate one standard deviation (SD).
The multivariable linear regression models predicted 15%, 21% and 20% of the overall variance in trabecular and cortical vBMD of femoral neck and vBMD of lumbar spine, respectively. Diabetes was associated with a 16.5% greater trabecular vBMD at the femoral neck and, 11% lumbar spine, but <2% for cortical vBMD. For femoral neck trabecular vBMD, the strongest negative correlates were past smoking (-9%), fracture history (-15%), kidney stones (-7%), corticosteroids (-11%) and insulin therapy (-26%). For cortical vBMD, the strongest negative correlate was use of thyroid medication (-2.8%). The strongest negative correlates for lumbar spine trabecular vBMD were fracture history (-5%), anti-androgen use (-19%), height (-8%) and thiazoliainediones use (-22%). Bioavailable estradiol and testosterone levels were positively related and sex hormone binding globulin, negatively related to trabecular vBMD of the spine. There was no relationship between sex hormones and femoral neck trabecular vBMD.
Correlates of trabecular vBMD and cortical vBMD appear to differ in older men.
PMCID: PMC3727421  PMID: 20572023
male osteoporosis; volumetric bone mineral density; areal bone mineral density; trabecular bone; cortical bone
11.  Abnormal Microarchitecture and Reduced Stiffness at the Radius and Tibia in Postmenopausal Women With Fractures 
Journal of Bone and Mineral Research  2010;25(12):2572-2581.
Measurement of areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry (DXA) has been shown to predict fracture risk. High-resolution peripheral quantitative computed tomography (HR-pQCT) yields additional information about volumetric BMD (vBMD), microarchitecture, and strength that may increase understanding of fracture susceptibility. Women with (n = 68) and without (n = 101) a history of postmenopausal fragility fracture had aBMD measured by DXA and trabecular and cortical vBMD and trabecular microarchitecture of the radius and tibia measured by HR-pQCT. Finite-element analysis (FEA) of HR-pQCT scans was performed to estimate bone stiffness. DXA T-scores were similar in women with and without fracture at the spine, hip, and one-third radius but lower in patients with fracture at the ultradistal radius (p < .01). At the radius fracture, patients had lower total density, cortical thickness, trabecular density, number, thickness, higher trabecular separation and network heterogeneity (p < .0001 to .04). At the tibia, total, cortical, and trabecular density and cortical and trabecular thickness were lower in fracture patients (p < .0001 to .03). The differences between groups were greater at the radius than at the tibia for inner trabecular density, number, trabecular separation, and network heterogeneity (p < .01 to .05). Stiffness was reduced in fracture patients, more markedly at the radius (41% to 44%) than at the tibia (15% to 20%). Women with fractures had reduced vBMD, microarchitectural deterioration, and decreased strength. These differences were more prominent at the radius than at the tibia. HR-pQCT and FEA measurements of peripheral sites are associated with fracture prevalence and may increase understanding of the role of microarchitectural deterioration in fracture susceptibility. © 2010 American Society for Bone and Mineral Research.
PMCID: PMC3149820  PMID: 20564238
12.  Abnormal Microarchitecture and Reduced Stiffness at the Radius and Tibia in Postmenopausal Women With Fractures 
Measurement of areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry (DXA) has been shown to predict fracture risk. High-resolution peripheral quantitative computed tomography (HR-pQCT) yields additional information about volumetric BMD (vBMD), microarchitecture, and strength that may increase understanding of fracture susceptibility. Women with (n = 68) and without (n = 101) a history of postmenopausal fragility fracture had aBMD measured by DXA and trabecular and cortical vBMD and trabecular microarchitecture of the radius and tibia measured by HR-pQCT. Finite-element analysis (FEA) of HR-pQCT scans was performed to estimate bone stiffness. DXA T-scores were similar in women with and without fracture at the spine, hip, and one-third radius but lower in patients with fracture at the ultradistal radius (p <.01). At the radius fracture, patients had lower total density, cortical thickness, trabecular density, number, thickness, higher trabecular separation and network heterogeneity (p <.0001 to .04). At the tibia, total, cortical, and trabecular density and cortical and trabecular thickness were lower in fracture patients (p <.0001 to .03). The differences between groups were greater at the radius than at the tibia for inner trabecular density, number, trabecular separation, and network heterogeneity (p <.01 to .05). Stiffness was reduced in fracture patients, more markedly at the radius (41% to 44%) than at the tibia (15% to 20%). Women with fractures had reduced vBMD, microarchitectural deterioration, and decreased strength. These differences were more prominent at the radius than at the tibia. HR-pQCT and FEA measurements of peripheral sites are associated with fracture prevalence and may increase understanding of the role of microarchitectural deterioration in fracture susceptibility.
PMCID: PMC3149820  PMID: 20564238
13.  Follicle-stimulating hormone and bioavailable estradiol are less important than weight and race in determining bone density in younger postmenopausal women 
The association between follicle-stimulating hormone (FSH) and bone density was tested in 111 postmenopausal women aged 50–64 years. In the multivariable analysis, weight and race were important determinants of bone mineral density. FSH, bioavailable estradiol, and other hormonal variables did not show statistically significant associations with bone density at any site.
FSH has been associated with bone density loss in animal models and longitudinal studies of women. Most of these analyses have not considered the effect of weight or race.
We tested the association between FSH and bone density in younger postmenopausal women, adjusting for patient-related factors. In 111 postmenopausal women aged 50–64 years, areal bone mineral density (BMD) was measured at the lumbar spine, femoral neck, total hip, and distal radius using dual-energy X-ray absorptiometry, and volumetric BMD was measured at the distal radius using peripheral quantitative computed tomography (pQCT). Height, weight, osteoporosis risk factors, and serum hormonal factors were assessed.
FSH inversely correlated with weight, bioavailable estradiol, areal BMD at the lumbar spine and hip, and volumetric BMD at the ultradistal radius. In the multivariable analysis, no hormonal variable showed a statistically significant association with areal BMD at any site. Weight was independently associated with BMD at all central sites (p<0.001), but not with BMD or pQCT measures at the distal radius. Race was independently associated with areal BMD at all sites (p≤0.008) and with cortical area at the 33% distal radius (p=0.004).
Correlations between FSH and bioavailable estradiol and BMD did not persist after adjustment for weight and race in younger postmenopausal women. Weight and race were more important determinants of bone density and should be included in analyses of hormonal influences on bone.
PMCID: PMC3109215  PMID: 21125395
Bone densitometry; Bone QCT; Hormones and receptors; Menopause; Osteoporosis
14.  Reduced bone mineral density in young adults following cure of acute lympblastic leukaemia in childhood 
British Journal of Cancer  1999;79(11-12):1859-1863.
Bone mineral density (BMD), serum osteocalcin and type I collagen C-telopeptide (ICTP) were assessed in a cohort of 31 (16 males) adults who had received cranial irradiation in childhood as part of their treatment for acute lymphoblastic leukaemia (ALL). Markers of bone turnover were compared with those of 35 age and body mass index (BMI) matched young adults (18 male). Growth hormone status had previously been determined using an insulin tolerance test and arginine stimulation test. Eight patients were classified as severe growth hormone deficiency (group 1), 12 patients as growth hormone insufficient (group 2) and 11 patients as normal (group 3). Vertebral trabecular BMD, lumbar spine and femoral neck integral BMD and forearm cortical bone mineral content (BMC) was measured 17.8 (6.8–28.6) years after cranial irradiation and was expressed as Z (standard deviation) scores. There was a significant reduction in vertebral trabecular BMD (median Z score –1.25, P < 0.001), in lumbar spine integral BMD (median Z score –0.74, P = 0.001), in forearm cortical BMC (median Z score –1.35, P < 0.001), and less so in femoral neck integral BMD (median Z score –0.43, P = 0.03). There was no difference among the growth hormone status groups for the following BMD measurements: vertebral trabecular BMD, lumbar spine integral BMD or femoral neck integral BMD (P = 0.8, P = 0.96 and P = 0.4 respectively). There was only a marginal significant difference for BMD at the wrist between growth hormone status groups (P = 0.04). There was no correlation between the BMD measurements with time since or age at diagnosis and no difference in markers of bone turnover between patients and controls; median serum osteocalcin 13.3 and 12.0 ng ml (P = 0.7), respectively, and for ICTP 5.0 and 4.9 μg L (P = 0.67) respectively. In conclusion, there is a highly significant reduction in BMD in young adults following treatment for ALL in childhood. The reduction in BMD affects both trabecular and cortical bone but did not seem to be related to time since diagnosis, age at diagnosis, or current growth hormone status. Possible explanations include a direct effect of chemotherapy, steroids or both on bone during childhood and hence an effect on the accretion of bone mass. In view of the risk of fractures in patients with osteopenia, adults treated for ALL in childhood may be at an increased risk of bone fractures later in life irrespective of the underlying cause of the osteopenia and thus intervention should be considered. © 1999 Cancer Research Campaign
PMCID: PMC2362787  PMID: 10206305
bone mineral density; acute lymphoblastic leukaemia
15.  Genetic Determinants of Trabecular and Cortical Volumetric Bone Mineral Densities and Bone Microstructure 
PLoS Genetics  2013;9(2):e1003247.
Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n = 5,878) followed by replication (n = 1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p = 3.6×10−14; LOC285735, rs271170, p = 2.7×10−12; OPG, rs7839059, p = 1.2×10−10; and ESR1/C6orf97, rs6909279, p = 1.1×10−9). The trabecular vBMD GWA meta-analysis (n = 2,500) followed by replication (n = 1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p = 1.9×10−9). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n = 729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60–0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.
Author Summary
Osteoporosis is a common highly heritable skeletal disease characterized by reduced bone mineral density (BMD) and deteriorated bone microstructure, resulting in an increased risk of fracture. Most previous genetic epidemiology studies have focused on the genetics of the complex trait BMD, not being able to separate genetic determinants of the trabecular and cortical bone compartments and bone microstructure. The trabecular and cortical BMDs can be analysed separately by computed tomography. Therefore, we performed separate genome-wide association studies for trabecular and cortical BMDs, demonstrating that the genetic determinants of cortical and trabecular BMDs differ. Genetic variants in the RANKL, LOC285735, OPG, and ESR1 loci were associated with cortical BMD, while a genetic variant in the FMN2/GREM2 locus was associated with trabecular BMD. Two of these are novel bone-related loci. Follow-up analyses of bone microstructure demonstrated that a genetic variant in the RANKL locus is associated with cortical porosity and that the FMN2/GREM2 locus is associated with trabecular number and thickness. We propose that a genetic variant in the RANKL locus influences cortical BMD via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences trabecular BMD and fracture risk via effects on both trabecular number and thickness.
PMCID: PMC3578773  PMID: 23437003
16.  Influence of Polymorphisms in the RANKL/RANK/OPG Signaling Pathway on Volumetric Bone Mineral Density and Bone Geometry at the Forearm in Men 
Calcified Tissue International  2011;89(6):446-455.
We sought to determine the influence of single-nucleotide polymorphisms (SNPs) in RANKL, RANK, and OPG on volumetric bone mineral density (vBMD) and bone geometry at the radius in men. Pairwise tag SNPs (r2 ≥ 0.8) for RANKL (n = 8), RANK (n = 44), and OPG (n = 22) and five SNPs near RANKL and OPG strongly associated with areal BMD in genomewide association studies were previously genotyped in men aged 40–79 years in the European Male Ageing Study (EMAS). Here, these SNPs were analyzed in a subsample of men (n = 589) who had peripheral quantitative computed tomography (pQCT) performed at the distal (4%) and mid-shaft (50%) radius. Estimated parameters were total and trabecular vBMD (mg/mm3) and cross-sectional area (mm2) at the 4% site and cortical vBMD (mg/mm3); total, cortical, and medullary area (mm2); cortical thickness (mm); and stress strain index (SSI) (mm3) at the 50% site. We identified 12 OPG SNPs associated with vBMD and/or geometric parameters, including rs10505348 associated with total vBMD (β [95% CI] = 9.35 [2.12–16.58], P = 0.011), cortical vBMD (β [95% CI] = 5.62 [2.10–9.14], P = 0.002), cortical thickness (β [95% CI] = 0.08 [0.03–0.13], P = 0.002), and medullary area (β [95% CI] = −2.90 [−4.94 to −0.86], P = 0.005) and rs2073618 associated with cortical vBMD (β [95% CI] = −4.30 [−7.78 to −0.82], P = 0.015) and cortical thickness (β [95% CI] = −0.08 [−0.13 to −0.03], P = 0.001). Three RANK SNPs were associated with vBMD, including rs12956925 associated with trabecular vBMD (β [95% CI] = −7.58 [−14.01 to −1.15], P = 0.021). There were five RANK SNPs associated with geometric parameters, including rs8083511 associated with distal radius cross-sectional area (β [95% CI] = 8.90 [0.92–16.88], P = 0.029). No significant association was observed between RANKL SNPs and pQCT parameters. Our findings suggest that genetic variation in OPG and RANK influences radius vBMD and geometry in men.
Electronic supplementary material
The online version of this article (doi:10.1007/s00223-011-9532-y) contains supplementary material, which is available to authorized users.
PMCID: PMC3215872  PMID: 21964949
Osteoporosis; Genetic association; Genetic polymorphism; Male; QCT
17.  Assessment of Incident Spine and Hip Fractures in Women and Men using Finite Element Analysis of CT Scans 
Finite element analysis of computed tomography (CT) scans provides non-invasive estimates of bone strength at the spine and hip. To further validate such estimates clinically, we performed a five-year case-control study of 1110 women and men over age 65 from the AGES-Reykjavik cohort (case = incident spine or hip fracture; control = no incident spine or hip fracture, respectively). From the baseline CT scans, we measured femoral and vertebral strength, as well as bone mineral density (BMD) at the hip (areal BMD only) and lumbar spine (trabecular volumetric BMD only). We found that, for incident radiographically-confirmed spine fractures (n=167), the age-adjusted odds ratio for vertebral strength was significant for women (2.8, 95% CI: 1.8–4.3) and men (2.2, 95% CI: 1.5–3.2), and for men, remained significant (p=0.01) independent of vertebral trabecular volumetric BMD. For incident hip fractures (n=171), the age-adjusted odds ratio for femoral strength was significant for women (4.2, 95% CI: 2.6–6.9) and men (3.5, 95% CI: 2.3–5.3) and remained significant after adjusting for femoral neck areal BMD in women and for total hip areal BMD in both sexes; fracture classification improved for women by combining femoral strength with femoral neck areal BMD (p=0.002). For both sexes, the probabilities of spine and hip fractures were similarly high at the BMD-based interventional thresholds for osteoporosis and at corresponding pre-established thresholds for “fragile bone strength” (spine: women ≤ 4,500 N, men ≤ 6,500 N; hip: women ≤ 3,000 N, men ≤ 3,500 N). Since it is well established that individuals over age 65 who have osteoporosis at the hip or spine by BMD criteria should be considered at high risk of fracture, these results indicate that individuals who have “fragile bone strength” at the hip or spine should also be considered at high risk of fracture.
PMCID: PMC3925753  PMID: 23956027
osteoporosis; fracture risk assessment; biomechanics; bone QCT
18.  Skeletal Structure in Postmenopausal Women with Osteopenia and Fractures is Characterized by Abnormal Trabecular Plates and Cortical Thinning 
The majority of fragility fractures occur in women with osteopenia rather than osteoporosis by dual energy x-ray absorptiometry (DXA). However, it is difficult to identify which women with osteopenia are at greatest risk. We performed this study to determine whether osteopenic women with and without fracture had differences in trabecular morphology and biomechanical properties of bone. We hypothesized that women with fractures would have fewer trabecular plates, less trabecular connectivity and lower stiffness. We enrolled 117 postmenopausal women with osteopenia by DXA (mean age 66 years; 58 with fragility fractures and 59 non-fractured controls). All had areal bone mineral density by DXA. Trabecular and cortical volumetric BMD (vBMD), trabecular microarchitecture, and cortical porosity were measured by high resolution peripheral computed tomography (HR-pQCT) of the distal radius and tibia. HR-pQCT scans were subjected to finite element analysis to estimate whole bone stiffness and individual trabecula segmentation (ITS) to evaluate trabecular type (as plate or rod), orientation and connectivity. Groups had similar age, race, BMI, and mean T-scores. Fracture subjects had lower cortical and trabecular vBMD, thinner cortices, and thinner more widely separated trabeculae. By ITS, fracture subjects had fewer trabecular plates, less axially aligned trabeculae and less trabecular connectivity. Whole bone stiffness was lower in women with fractures. Cortical porosity did not differ. Differences in cortical bone were found at both sites, whereas trabecular differences were more pronounced at the radius. In summary, postmenopausal women with osteopenia and fractures had lower cortical and trabecular vBMD, thinner, more widely separated and rod-like trabecular structure, less trabecular connectivity and lower whole bone stiffness compared to controls, despite similar aBMD by DXA. Our results suggest that in addition to trabecular and cortical bone loss, changes in plate and rod structure may be important mechanisms of fracture in postmenopausal women with osteopenia.
PMCID: PMC4084559  PMID: 24877245
Osteoporosis; fracture; microarchitecture; bone quality; menopause
19.  Automated simulation of areal bone mineral density assessment in the distal radius from high-resolution peripheral quantitative computed tomography 
Osteoporosis International  2009;20(12):2017-2024.
An automated image processing method is presented for simulating areal bone mineral density measures using high-resolution peripheral quantitative computed tomography (HR-pQCT) in the ultra-distal radius. The accuracy of the method is validated against clinical dual X-ray absorptiometry (DXA). This technique represents a useful reference to gauge the utility of novel 3D quantification methods applied to HR-pQCT in multi-center clinical studies and potentially negates the need for separate forearm DXA measurements.
Osteoporotic status is primarily assessed by measuring areal bone mineral density (aBMD) using 2D dual X-ray absorptiometry (DXA). However, this technique does not sufficiently explain bone strength and fracture risk. High-resolution peripheral quantitative computed tomography (HR-pQCT) has been introduced as a method to quantify 3D bone microstructure and biomechanics. In this study, an automated method is proposed to simulate aBMD measures from HR-pQCT distal radius images.
A total of 117 subject scans were retrospectively analyzed from two clinical bone quality studies. The distal radius was imaged by HR-pQCT and DXA on one of two devices (Hologic or Lunar). Areal BMD was calculated by simulation from HR-pQCT images (aBMDsim) and by standard DXA analysis (aBMDdxa).
The reproducibility of the simulation technique was 1.1% (root mean-squared coefficient of variation). HR-pQCT-based aBMDsim correlated strongly to aBMDdxa (Hologic: R2 = 0.82, Lunar: R2 = 0.87), though aBMDsim underestimated aBMDdxa for both DXA devices (p < 0.0001). Finally, aBMDsim predicted aBMD at the proximal femur and lumbar spine with equal power compared to aBMDdxa.
The results demonstrate that aBMD can be simulated from HR-pQCT images of the distal radius. This approach has the potential to serve as a surrogate forearm aBMD measure for clinical HR-pQCT studies when axial bone mineral density values are not required.
PMCID: PMC2777210  PMID: 19330422
Bone mineral density; DXA; HR-pQCT; Osteoporosis; Simulation
20.  Use of SSRIs may Impact Bone Density in Adolescent and Young Women with Anorexia Nervosa 
CNS spectrums  2010;15(9):579-586.
Alterations in serotonin impact bone metabolism in animal models, and selective serotonin reuptake inhibitors (SSRI) have been associated with increased fracture risk in older adults. SSRIs are commonly used in anorexia nervosa (AN), a condition that predisposes to low bone mineral density (BMD). Our objective was to determine whether SSRI use is associated with low BMD in AN.
We examined Z-scores for spine, hip and whole body (WB) BMD, spine bone mineral apparent density and WBBMC/height (Ht) in females with AN 12-21 years old who had never been on SSRIs, on SSRIs for <6 months (<6M) or >6 months (>6M).
Subjects on SSRIs for >6M had lower spine, femoral-neck and WBBMD Z-scores than those on SSRIs for <6M. Hip BMD and WBBMC/Ht Z-scores were lowest in subjects on SSRIs for >6M. Duration of SSRI use, duration since AN diagnosis and duration of amenorrhea inversely predicted BMD, whereas BMI was a positive predictor. In a regression model, duration of SSRI use remained an independent negative predictor of BMD.
Duration of SSRI use >6M is associated with low BMD in AN.
It may be necessary to monitor BMD more rigorously when duration of SSRI use exceeds 6M.
PMCID: PMC4001118  PMID: 24790401
Anorexia nervosa; SSRIs; serotonin; bone density; selective serotonin reuptake inhibitors
21.  Decreased Bone Mineral Density in Adults Born with Very Low Birth Weight: A Cohort Study 
PLoS Medicine  2009;6(8):e1000135.
Petteri Hovi and colleagues evaluate skeletal health in 144 adults born preterm with very low birth weight and show that as adults these individuals have significantly lower bone mineral density than do their term-born peers.
Very-low-birth-weight (VLBW, <1,500 g) infants have compromised bone mass accrual during childhood, but it is unclear whether this results in subnormal peak bone mass and increased risk of impaired skeletal health in adulthood. We hypothesized that VLBW is associated with reduced bone mineral density (BMD) in adulthood.
Methods and Findings
The Helsinki Study of Very Low Birth Weight Adults is a multidisciplinary cohort study representative of all VLBW births within the larger Helsinki area from 1978 to 1985. This study evaluated skeletal health in 144 such participants (all born preterm, mean gestational age 29.3 wk, birth weight 1,127 g, birth weight Z score 1.3), and in 139 comparison participants born at term, matched for sex, age, and birth hospital. BMD was measured by dual energy X-ray absorptiometry at age 18.5 to 27.1 y. Adults born with VLBW had, in comparison to participants born at term, a 0.51-unit (95% confidence interval [CI] 0.28–0.75) lower lumbar spine Z score and a 0.56-unit (95% CI 0.34–0.78) lower femoral neck Z score for areal BMD. These differences remained statistically significant after adjustment for the VLBW adults' shorter height and lower self-reported exercise intensity.
Young adults born with VLBW, when studied close to the age of peak bone mass, have significantly lower BMD than do their term-born peers. This suggests that compromised childhood bone mass accrual in preterm VLBW children translates into increased risk for osteoporosis in adulthood, warranting vigilance in osteoporosis prevention.
Please see later in the article for the Editors' Summary
Editors' Summary
Most pregnancies last 40 weeks but some babies arrive earlier than expected. Sadly, babies born before 37 weeks of pregnancy—premature babies—are more likely to die than full-term babies, although recent improvements in neonatal care have increased their chances of survival. Premature babies also often have serious long-term health problems, particularly those born before 32 weeks of pregnancy. Such extremely premature babies have poorly developed internal organs and are usually very small—babies whose birth weight is less than 1,500 g are called very-low-birth-weight (VLBW) babies; the average full-term birth weight is about 3,500 g. Furthermore, their bones are not as well developed as those of full-term babies. The human skeleton initially consists of a soft fibrous material called cartilage. This is gradually transformed into bone by a process called bone mineralization. The last third of pregnancy is a crucial period for bone mineralization although the process continues throughout infancy and childhood. Thus, VLBW babies often have subnormal skeletal mineralization and their accrual of bone mass during childhood is frequently compromised.
Why Was This Study Done?
It is not known whether the childhood bone deficits of VLBW babies persist into adulthood because the first generation of these infants not to die soon after birth is only just reaching adulthood. Peak bone mass is reached in early adulthood (bone mass begins to decrease from the age of 35 years onward) and is an important indicator of whether an individual will develop osteoporosis (thinning of the bones) and be susceptible to bone fractures later in life. If adults with VLBW (about 1% of live births in high-income countries are now VLBW births) do have a subnormal peak bone mass and reduced bone mineral density (BMD), they may be able reduce their risk of developing osteoporosis by eating a healthy diet and exercising regularly. In this study (part of the Helsinki Study of Very Low Birth Weight Adults), the researchers investigate the skeletal health of people who were born with VLBW in the Helsinki area between 1978 and 1985.
What Did the Researchers Do and Find?
The researchers compared the skeletal health of 144 young adults who were born prematurely with VLBW and subnormal BMD with that of 139 age- and sex-matched individuals who were born at term. They measured the BMD of the participants (average age 22.6 years) using “dual energy X-ray absorptiometry” and determined a “Z score” for the spine in the lower back (the lower lumbar spine) and the hip (two sites that are routinely examined in assessments of skeletal health). Z scores indicate whether an individual's BMD is significantly different from the average BMD of healthy age- and sex-matched people; in this study, reduced BMD was defined as a Z score of −1.0 or less. The researchers found that adults born with VLBW had an average Z score of −0.51 at the lower lumbar spine and −0.56 at the hip when compared with the adults born at term. Furthermore, 44% of the VLBW participants but only 26% of the term-born participants had a lumbar spine Z score of −1.0 or less. Adjustment for the shorter height of the VLBW participants slightly reduced these differences in BMD but the differences remained statistically significant.
What Do These Findings Mean?
These findings show that, when studied close to the age of peak bone mass, young adults born with VLBW have a significantly lower BMD than their term-born peers and a 2-fold greater risk of having a lumbar spine Z score of below −1.0; a unit decrease in Z score approximately doubles the risk of bone fractures. Because BMD measurements were only taken at one age, it remains possible, however, that the BMD of the VLBW adults might eventually match that of their full-term peers. Recently born VLBW babies still have a lower than average BMD during their childhood, note the researchers, even though their care has changed since the people included in this study were born. Thus, these findings suggest that people who were VLBW infants should be encouraged to eat food rich in vitamin D and calcium and to do regular weight-bearing exercise throughout their lives to improve their bone health and reduce their risk of developing osteoporosis.
Additional Information
Please access these Web sites via the online version of this summary at
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
MedlinePlus provides links to other information on premature babies and to information on osteoporosis (in English and Spanish)
The US National Institute of Arthritis and Musculoskeletal and Skin Diseases and the UK National Health Service also provide detailed information on all aspects of osteoporosis
Further details about the Helsinki Study of Very Low Birth Weight Adults are available
PMCID: PMC2722726  PMID: 19707270
22.  Bone disease in primary hyperparathyrodism 
Nowadays, primary hyperparathyroidism (PHPT) is mostly a mild disease. Overt skeletal manifestations are rare but decreased bone mineral density (BMD) can still be demonstrated. Even in mild cases, excess parathyroid hormone (PTH) increases bone turnover leading to bone loss particularly at cortical sites. Conversely, a relative preservation of cancellous bone has been shown by histomorphometric analyses and advanced imaging techniques. An increased fracture rate has been demonstrated in untreated patients with PHPT at peripheral sites and in the spine. Parathyroidectomy (PTx) is the definitive cure for PHPT. With the restoration of normal PTH, bone resorption is quickly tapered down, while bone formation proceeds at the level of bone multicellular units, which were activated prior to PTx. The rapid refilling of the enlarged remodeling space and the subsequent matrix mineralization will result in an increase in BMD at sites rich in trabecular bone, such as lumbar spine and hip, which mainly occurs during the first 6–12 months after PTx. Cortical bone is less responsive to PTX because of the low rate of bone turnover, but sensible increases in BMD at the distal third of the radius can be observed in the long term. PTx seems to decrease the risk of fractures but more data are needed before a definitive conclusion on this important matter can be reached. Treatment with bisphosphonates can be considered for patients with low BMD who do not undergo PTx. Two-year treatment with alendronate has been shown to decrease bone turnover markers and increase BMD at the lumbar spine and hip, but not at the distal radius. Cinacalcet stably decreased serum calcium levels across a broad range of PHPT severity, but no change in BMD occurred in patients treated for up to 5.5 years.
PMCID: PMC3458615  PMID: 23024712
bisphosphonates; bone markers; bone mineral density; calcimimetics; histomorphometry; osteitis fibrosa cystica; parathyroidectomy; parathyroid hormone
23.  Utilization of DXA Bone Mineral Densitometry in Ontario 
Executive Summary
Systematic reviews and analyses of administrative data were performed to determine the appropriate use of bone mineral density (BMD) assessments using dual energy x-ray absorptiometry (DXA), and the associated trends in wrist and hip fractures in Ontario.
Dual Energy X-ray Absorptiometry Bone Mineral Density Assessment
Dual energy x-ray absorptiometry bone densitometers measure bone density based on differential absorption of 2 x-ray beams by bone and soft tissues. It is the gold standard for detecting and diagnosing osteoporosis, a systemic disease characterized by low bone density and altered bone structure, resulting in low bone strength and increased risk of fractures. The test is fast (approximately 10 minutes) and accurate (exceeds 90% at the hip), with low radiation (1/3 to 1/5 of that from a chest x-ray). DXA densitometers are licensed as Class 3 medical devices in Canada. The World Health Organization has established criteria for osteoporosis and osteopenia based on DXA BMD measurements: osteoporosis is defined as a BMD that is >2.5 standard deviations below the mean BMD for normal young adults (i.e. T-score <–2.5), while osteopenia is defined as BMD that is more than 1 standard deviation but less than 2.5 standard deviation below the mean for normal young adults (i.e. T-score< –1 & ≥–2.5). DXA densitometry is presently an insured health service in Ontario.
Clinical Need
Burden of Disease
The Canadian Multicenter Osteoporosis Study (CaMos) found that 16% of Canadian women and 6.6% of Canadian men have osteoporosis based on the WHO criteria, with prevalence increasing with age. Osteopenia was found in 49.6% of Canadian women and 39% of Canadian men. In Ontario, it is estimated that nearly 530,000 Ontarians have some degrees of osteoporosis. Osteoporosis-related fragility fractures occur most often in the wrist, femur and pelvis. These fractures, particularly those in the hip, are associated with increased mortality, and decreased functional capacity and quality of life. A Canadian study showed that at 1 year after a hip fracture, the mortality rate was 20%. Another 20% required institutional care, 40% were unable to walk independently, and there was lower health-related quality of life due to attributes such as pain, decreased mobility and decreased ability to self-care. The cost of osteoporosis and osteoporotic fractures in Canada was estimated to be $1.3 billion in 1993.
Guidelines for Bone Mineral Density Testing
With 2 exceptions, almost all guidelines address only women. None of the guidelines recommend blanket population-based BMD testing. Instead, all guidelines recommend BMD testing in people at risk of osteoporosis, predominantly women aged 65 years or older. For women under 65 years of age, BMD testing is recommended only if one major or two minor risk factors for osteoporosis exist. Osteoporosis Canada did not restrict its recommendations to women, and thus their guidelines apply to both sexes. Major risk factors are age greater than or equal to 65 years, a history of previous fractures, family history (especially parental history) of fracture, and medication or disease conditions that affect bone metabolism (such as long-term glucocorticoid therapy). Minor risk factors include low body mass index, low calcium intake, alcohol consumption, and smoking.
Current Funding for Bone Mineral Density Testing
The Ontario Health Insurance Program (OHIP) Schedule presently reimburses DXA BMD at the hip and spine. Measurements at both sites are required if feasible. Patients at low risk of accelerated bone loss are limited to one BMD test within any 24-month period, but there are no restrictions on people at high risk. The total fee including the professional and technical components for a test involving 2 or more sites is $106.00 (Cdn).
Method of Review
This review consisted of 2 parts. The first part was an analysis of Ontario administrative data relating to DXA BMD, wrist and hip fractures, and use of antiresorptive drugs in people aged 65 years and older. The Institute for Clinical Evaluative Sciences extracted data from the OHIP claims database, the Canadian Institute for Health Information hospital discharge abstract database, the National Ambulatory Care Reporting System, and the Ontario Drug Benefit database using OHIP and ICD-10 codes. The data was analyzed to examine the trends in DXA BMD use from 1992 to 2005, and to identify areas requiring improvement.
The second part included systematic reviews and analyses of evidence relating to issues identified in the analyses of utilization data. Altogether, 8 reviews and qualitative syntheses were performed, consisting of 28 published systematic reviews and/or meta-analyses, 34 randomized controlled trials, and 63 observational studies.
Findings of Utilization Analysis
Analysis of administrative data showed a 10-fold increase in the number of BMD tests in Ontario between 1993 and 2005.
OHIP claims for BMD tests are presently increasing at a rate of 6 to 7% per year. Approximately 500,000 tests were performed in 2005/06 with an age-adjusted rate of 8,600 tests per 100,000 population.
Women accounted for 90 % of all BMD tests performed in the province.
In 2005/06, there was a 2-fold variation in the rate of DXA BMD tests across local integrated health networks, but a 10-fold variation between the county with the highest rate (Toronto) and that with the lowest rate (Kenora). The analysis also showed that:
With the increased use of BMD, there was a concomitant increase in the use of antiresorptive drugs (as shown in people 65 years and older) and a decrease in the rate of hip fractures in people age 50 years and older.
Repeat BMD made up approximately 41% of all tests. Most of the people (>90%) who had annual BMD tests in a 2-year or 3-year period were coded as being at high risk for osteoporosis.
18% (20,865) of the people who had a repeat BMD within a 24-month period and 34% (98,058) of the people who had one BMD test in a 3-year period were under 65 years, had no fracture in the year, and coded as low-risk.
Only 19% of people age greater than 65 years underwent BMD testing and 41% received osteoporosis treatment during the year following a fracture.
Men accounted for 24% of all hip fractures and 21 % of all wrist fractures, but only 10% of BMD tests. The rates of BMD tests and treatment in men after a fracture were only half of those in women.
In both men and women, the rate of hip and wrist fractures mainly increased after age 65 with the sharpest increase occurring after age 80 years.
Findings of Systematic Review and Analysis
Serial Bone Mineral Density Testing for People Not Receiving Osteoporosis Treatment
A systematic review showed that the mean rate of bone loss in people not receiving osteoporosis treatment (including postmenopausal women) is generally less than 1% per year. Higher rates of bone loss were reported for people with disease conditions or on medications that affect bone metabolism. In order to be considered a genuine biological change, the change in BMD between serial measurements must exceed the least significant change (variability) of the testing, ranging from 2.77% to 8% for precisions ranging from 1% to 3% respectively. Progression in BMD was analyzed, using different rates of baseline BMD values, rates of bone loss, precision, and BMD value for initiating treatment. The analyses showed that serial BMD measurements every 24 months (as per OHIP policy for low-risk individuals) is not necessary for people with no major risk factors for osteoporosis, provided that the baseline BMD is normal (T-score ≥ –1), and the rate of bone loss is less than or equal to 1% per year. The analyses showed that for someone with a normal baseline BMD and a rate of bone loss of less than 1% per year, the change in BMD is not likely to exceed least significant change (even for a 1% precision) in less than 3 years after the baseline test, and is not likely to drop to a BMD level that requires initiation of treatment in less than 16 years after the baseline test.
Serial Bone Mineral Density Testing in People Receiving Osteoporosis Therapy
Seven published meta-analysis of randomized controlled trials (RCTs) and 2 recent RCTs on BMD monitoring during osteoporosis therapy showed that although higher increases in BMD were generally associated with reduced risk of fracture, the change in BMD only explained a small percentage of the fracture risk reduction.
Studies showed that some people with small or no increase in BMD during treatment experienced significant fracture risk reduction, indicating that other factors such as improved bone microarchitecture might have contributed to fracture risk reduction.
There is conflicting evidence relating to the role of BMD testing in improving patient compliance with osteoporosis therapy.
Even though BMD may not be a perfect surrogate for reduction in fracture risk when monitoring responses to osteoporosis therapy, experts advised that it is still the only reliable test available for this purpose.
A systematic review conducted by the Medical Advisory Secretariat showed that the magnitude of increases in BMD during osteoporosis drug therapy varied among medications. Although most of the studies yielded mean percentage increases in BMD from baseline that did not exceed the least significant change for a 2% precision after 1 year of treatment, there were some exceptions.
Bone Mineral Density Testing and Treatment After a Fragility Fracture
A review of 3 published pooled analyses of observational studies and 12 prospective population-based observational studies showed that the presence of any prevalent fracture increases the relative risk for future fractures by approximately 2-fold or more. A review of 10 systematic reviews of RCTs and 3 additional RCTs showed that therapy with antiresorptive drugs significantly reduced the risk of vertebral fractures by 40 to 50% in postmenopausal osteoporotic women and osteoporotic men, and 2 antiresorptive drugs also reduced the risk of nonvertebral fractures by 30 to 50%. Evidence from observational studies in Canada and other jurisdictions suggests that patients who had undergone BMD measurements, particularly if a diagnosis of osteoporosis is made, were more likely to be given pharmacologic bone-sparing therapy. Despite these findings, the rate of BMD investigation and osteoporosis treatment after a fracture remained low (<20%) in Ontario as well as in other jurisdictions.
Bone Mineral Density Testing in Men
There are presently no specific Canadian guidelines for BMD screening in men. A review of the literature suggests that risk factors for fracture and the rate of vertebral deformity are similar for men and women, but the mortality rate after a hip fracture is higher in men compared with women. Two bisphosphonates had been shown to reduce the risk of vertebral and hip fractures in men. However, BMD testing and osteoporosis treatment were proportionately low in Ontario men in general, and particularly after a fracture, even though men accounted for 25% of the hip and wrist fractures. The Ontario data also showed that the rates of wrist fracture and hip fracture in men rose sharply in the 75- to 80-year age group.
Ontario-Based Economic Analysis
The economic analysis focused on analyzing the economic impact of decreasing future hip fractures by increasing the rate of BMD testing in men and women age greater than or equal to 65 years following a hip or wrist fracture. A decision analysis showed the above strategy, especially when enhanced by improved reporting of BMD tests, to be cost-effective, resulting in a cost-effectiveness ratio ranging from $2,285 (Cdn) per fracture avoided (worst-case scenario) to $1,981 (Cdn) per fracture avoided (best-case scenario). A budget impact analysis estimated that shifting utilization of BMD testing from the low risk population to high risk populations within Ontario would result in a saving of $0.85 million to $1.5 million (Cdn) to the health system. The potential net saving was estimated at $1.2 million to $5 million (Cdn) when the downstream cost-avoidance due to prevention of future hip fractures was factored into the analysis.
Other Factors for Consideration
There is a lack of standardization for BMD testing in Ontario. Two different standards are presently being used and experts suggest that variability in results from different facilities may lead to unnecessary testing. There is also no requirement for standardized equipment, procedure or reporting format. The current reimbursement policy for BMD testing encourages serial testing in people at low risk of accelerated bone loss. This review showed that biannual testing is not necessary for all cases. The lack of a database to collect clinical data on BMD testing makes it difficult to evaluate the clinical profiles of patients tested and outcomes of the BMD tests. There are ministry initiatives in progress under the Osteoporosis Program to address the development of a mandatory standardized requisition form for BMD tests to facilitate data collection and clinical decision-making. Work is also underway for developing guidelines for BMD testing in men and in perimenopausal women.
Increased use of BMD in Ontario since 1996 appears to be associated with increased use of antiresorptive medication and a decrease in hip and wrist fractures.
Data suggest that as many as 20% (98,000) of the DXA BMD tests in Ontario in 2005/06 were performed in people aged less than 65 years, with no fracture in the current year, and coded as being at low risk for accelerated bone loss; this is not consistent with current guidelines. Even though some of these people might have been incorrectly coded as low-risk, the number of tests in people truly at low risk could still be substantial.
Approximately 4% (21,000) of the DXA BMD tests in 2005/06 were repeat BMDs in low-risk individuals within a 24-month period. Even though this is in compliance with current OHIP reimbursement policies, evidence showed that biannual serial BMD testing is not necessary in individuals without major risk factors for fractures, provided that the baseline BMD is normal (T-score < –1). In this population, BMD measurements may be repeated in 3 to 5 years after the baseline test to establish the rate of bone loss, and further serial BMD tests may not be necessary for another 7 to 10 years if the rate of bone loss is no more than 1% per year. Precision of the test needs to be considered when interpreting serial BMD results.
Although changes in BMD may not be the perfect surrogate for reduction in fracture risk as a measure of response to osteoporosis treatment, experts advised that it is presently the only reliable test for monitoring response to treatment and to help motivate patients to continue treatment. Patients should not discontinue treatment if there is no increase in BMD after the first year of treatment. Lack of response or bone loss during treatment should prompt the physician to examine whether the patient is taking the medication appropriately.
Men and women who have had a fragility fracture at the hip, spine, wrist or shoulder are at increased risk of having a future fracture, but this population is presently under investigated and under treated. Additional efforts have to be made to communicate to physicians (particularly orthopaedic surgeons and family physicians) and the public about the need for a BMD test after fracture, and for initiating treatment if low BMD is found.
Men had a disproportionately low rate of BMD tests and osteoporosis treatment, especially after a fracture. Evidence and fracture data showed that the risk of hip and wrist fractures in men rises sharply at age 70 years.
Some counties had BMD utilization rates that were only 10% of that of the county with the highest utilization. The reasons for low utilization need to be explored and addressed.
Initiatives such as aligning reimbursement policy with current guidelines, developing specific guidelines for BMD testing in men and perimenopausal women, improving BMD reports to assist in clinical decision making, developing a registry to track BMD tests, improving access to BMD tests in remote/rural counties, establishing mechanisms to alert family physicians of fractures, and educating physicians and the public, will improve the appropriate utilization of BMD tests, and further decrease the rate of fractures in Ontario. Some of these initiatives such as developing guidelines for perimenopausal women and men, and developing a standardized requisition form for BMD testing, are currently in progress under the Ontario Osteoporosis Strategy.
PMCID: PMC3379167  PMID: 23074491
24.  The Effects of Adiponectin and Leptin on Changes in Bone Mineral Density 
Adiponectin and leptin are hormones secreted by adipose cells that may impact bone mineral density (BMD). Few studies have evaluated the longitudinal association of leptin and adiponectin levels with rates of BMD change.
Hip and whole body areal BMD (aBMD) were measured 5 times using dual energy x-ray absorptiometry (DXA) over 10 years. Trabecular lumbar spine volumetric BMD (vBMD) was measured using quantitative computed topography (QCT) at baseline and year 6 in the Pittsburgh cohort only. Random slope and intercept models were used to account for within person correlation as a result of repeated measures of hip and whole body aBMD. Linear regression was used to model changes in spine trabecular vBMD.
Among women, the annualized rate of hip aBMD loss in the highest tertile of adiponectin was −0.67% (95% CI: −0.77, −0.58) compared to −0.43% (95% CI: −0.51, −0.35)] in the lowest tertile (p trend=0.019) after adjusting for age, race, BMI, diabetes, baseline hip aBMD, and weight change. In men, hip aBMD loss was greatest in the high adiponectin group (tertile 3), however this association was not significant, p trend=0.148. After adjusting for weight change in women, the association between higher leptin and lower hip aBMD loss was attenuated and no longer significant, p trend=0.134. Leptin and adiponectin levels were not associated with whole body aBMD or trabecular lumbar spine vBMD loss.
Adiponectin was associated with increased hip aBMD loss in women only; supporting evidence that adiponectin may have an important role in bone health.
PMCID: PMC3536828  PMID: 21877199
leptin; adiponectin; bone loss; hip aBMD; whole body aBMD; trabecular lumbar spine vBMD
25.  Variants of the dopamine D2 receptor and risperidone-induced hyperprolactinemia in children and adolescents 
Pharmacogenetics and genomics  2009;19(5):373-382.
To investigate the association between hyperprolactinemia and variants of the dopamine D2 receptor (DRD2) gene in children and adolescents in long-term treatment with risperidone.
Medically healthy 7–17-year-old patients chronically treated with risperidone but receiving no other antipsychotics were selected for a cross-sectional evaluation. Four DRD2 variants were genotyped and prolactin concentration was measured. Medication history was obtained from the medical record. The effect of the TaqIA variants of the DRD2 on the risk of risperidone-induced hyperprolactinemia was the primary outcome measure.
Hyperprolactinemia was present in 50% of 107 patients (87% males) treated with risperidone for an average of 2.9 years. Age, stage of sexual development, and the dose of risperidone independently predicted a higher prolactin concentration, whereas the dose of psychostimulants was negatively correlated with it. However, these four predictors became nonsignificant when risperidone serum concentration was entered into the model. Adverse events potentially related to hyperprolactinemia were more common in participants with elevated prolactin concentration in girls (45%) compared with boys (10%). After controlling for risperidone concentration and the dose of psychostimulants, the TaqIA A1 and the A-241G alleles were associated with higher prolactin concentration, whereas the -141C Ins/Del AQ1and C957T variants had no significant effect. In addition, adverse events potentially related to hyperprolactinemia were four times more common in TaqIA A1 allele carriers.
Prolactin concentration is closely related to central DRD2 blockade, as reflected by risperidone serum concentration. Furthermore, the TaqIA and A-241G variants of the DRD2 gene could be useful in predicting the emergence of hyperprolactinemia and its potential adverse events.
PMCID: PMC2699901  PMID: 19339912
adolescents; antipsychotics; children; dopamine receptors; DRD2; genetic variants; hyperprolactinemia; risperidone; TaqIA

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