Intravenous pamidronate treatment in children with moderate to severe osteogenesis imperfecta: assessment of indices of dual-energy X-ray absorptiometry and bone metabolic markers during the first year of therapy

Bisphosphonates are now widely used to treat children with osteogenesis imperfecta (OI). However, there are few published data following the initial evolution of changes in bone mass with such treatment. The purpose of the present study was to assess indices of skeletal size and total and regional bone mass in children with OI during the first year of their pamidronate therapy. Twenty-six children [11 males, age median 10.6 (range 3.2-15.5) years] with type III (n=9) or type IV (n=17) OI received intravenous pamidronate 1.0 mg/kg/day on 3 consecutive days, 3-monthly over a 1-year period. Bone mass assessed by dual energy X-ray absorptiometry, serum alkaline phosphatase (ALP) and urine type I collagen N-terminal telopepetide (NTX) were measured at each cycle. Lumbar (L2 to L4) vertebral height increased by median (interquartile range) 4.5% (7.3), area by 11.3% (19.3), bone mineral content (BMC) by 73.7% (50.4), and bone mineral density (BMD) by 48.7% (34.7), P<0.0001 during the first year of therapy. Total body bone area increased by 26.7% (26.3), total body BMC by 41.4% (44.5), and total body BMD by 8.8% (8.3), P<0.0001. Head bone area remained constant whilst head BMC and BMD increased. Pre-infusion U-NTX and S-ALP levels decreased progressively during the follow-up indicating reducing bone turnover rate during pamidronate therapy. Increased bone area and mineral mass were observed during the first year of intravenous pamidronate therapy in children with OI. Increased head bone mass implies a direct effect of pamidronate on skeletal mass accretion, rather than an indirect effect mediated through increased physical activity.     

Two-year clinical trial of oral alendronate versus intravenous pamidronate in children with osteogenesis imperfecta.

A 2-year prospective, partially randomized open-label trial comparing oral alendronate with intravenous pamidronate therapy in children with OI showed equivalence in increasing total body BMD, spine BMD, and linear growth, and decreasing bone turnover and fracture incidence. Children with mild OI had greater responses than severe OI in BMD and growth. INTRODUCTION: Bisphosphonate therapies increase BMD and may reduce fractures in children with osteogenesis imperfecta (OI). A study directly comparing oral with intravenous bisphosphonate has not been published. This clinical trial compares oral alendronate with intravenous pamidronate in children with OI using an open-label, prospective, 2-year, randomized design. MATERIALS AND METHODS: Children over the age of 3 years were stratified by bone age, pubertal stage, and type of OI and then randomized to receive oral alendronate 1 mg/kg/day in tablet form or intravenous pamidronate, 3 mg/kg/4 months. One child was assigned to pamidronate. One child randomized to intravenous pamidronate changed to oral alendronate. Eighteen children completed 12 months of therapy: nine on oral alendronate and nine on intravenous pamidronate. Primary outcome efficacy was increase in BMD. Secondary outcomes included changes in bone turnover biomarkers, fracture incidence, and growth. RESULTS: Total body and lumbar spine BMD increased, turnover markers decreased, and linear growth increased equivalently with oral and intravenous therapy. Fracture incidence showed a trend to decrease in both groups, with a significant decrease in fracture rates when the oral and intravenous groups were pooled. There were greater responses in BMD and growth in children with milder OI (type I) than those with more severe disease (types III and IV), but there were no significant effects of age or pubertal stage. CONCLUSIONS: Oral and intravenous bisphosphonate therapies are equally effective in children with OI and are particularly effective in milder forms. The oral route is highly acceptable in children and has practical advantages over the intravenous route.     

Functional analysis of upper limb deformities in osteogenesis imperfecta

The charts and radiographs of 159 children with osteogenesis imperfecta (OI) were retrospectively reviewed to measure the severity of upper limb deformities and to evaluate the functional outcome using the Pediatric Evaluation of Disability Inventory (PEDI). The patients were classified according to the Sillence classification modified by Glorieux: 51 type 1, 33 type 3, 54 type 4, and 21 5ype 5. Fifty-nine patients (37.1%) had deformities of their upper limbs. Children with type 3 OI had the highest incidence and the most severe deformities. The humerus was the most commonly involved bone, followed by the ulna and radius. Upper limb deformities were classified into four groups according to the severity of the maximum deformity angle. The mean self-care scores of PEDI were significantly low only in the group with severe deformities, but mobility scores were dramatically decreased in both the moderate and severe deformity groups. Therefore, upper limb deformities in children with OI do not represent only a cosmetic problem, but may also significantly impair functional activities of daily living.     

Spinal complications in osteogenesis imperfecta 47 patients 1-16 years of age

We examined in a cross-sectional study, 47 children (mean age 7.7 (1-16) years) with osteogenesis imperfecta (OI) to find the prevalence of spinal deformities and to correlate these observations with anthropometry. The associations between dentinogenesis imperfecta, joint hypermobility and spinal deformities were also studied.

Disproportion in stature in OI type I and type IV was mainly caused by spinal involvement, as evidenced by a greater decrease in body height than in leg length. In OI type I, the decrease in sitting height was mainly caused by platyspondyly, whereas in OI types III and IV, it was also caused by progressive scoliosis and kyphosis. Scoliosis was present in 22 children, and pathological kyphosis in 18, mainly in the severe OI types. Basilar impression was observed in 10 children, mainly in type III.

Children with dentinogenesis imperfecta seemed to be prone to develop scoliosis, pathological kyphosis and basilar impression. Children with generalized joint hypermobility were less prone to develop scoliosis and basilar impression. Our observations may contribute to a better understanding of the risk factors for progressive spinal deformities in OI.     

Teriparatide Treatment in Adult Patients with Osteogenesis Imperfecta Type I

Osteogenesis imperfecta (OI) is a hereditary disease characterized by low bone mass, increased bone fragility, short stature, and skeletal deformities. This study focuses on OI type I, the mildest form of the disease. Bisphosphonates represent the prevailing standard of care in patients with OI. Teriparatide (TPD) is a PTH analog with bone-anabolic actions which has been approved for osteoporosis treatment. Thirteen postmenopausal women with type I OI who had been on treatment with neridronate for at least 2 years and who incurred new vertebral fracture during treatment were treated with TPD for 18 months. Bone mineral density (BMD) increased significantly over 18 months up to 3.5 % at the lumbar spine (p = 0.001), while no significant changes were noted in hip BMD. Serum markers of bone formation and of bone resorption increased significantly during the treatment. The Wnt inhibitors serum dickkopf-1 (DKK1) and sclerostin were also measured. A nonsignificant increase was seen in serum sclerostin levels, while serum DKK1 rose gradually and significantly during TPD treatment. In patients affected by type I OI, TPD treatment is associated with a remarkable response in markers of bone formation. This suggests a normal osteoblastic response to TPD. However, the observed increases in BMD were somewhat lower than those in postmenopausal or senile osteoporosis treated with TPD for the same lag time. Our results open the possibility to develop TPD for the treatment of adult type I OI, but particularly for the lack of a control group, a properly designed controlled study is warranted.     

Evidence for a Role for Nanoporosity and Pyridinoline Content in Human Mild Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous connective tissue disorder characterized by bone fragility that arises from decreased bone mass and abnormalities in bone material quality. OI type I represents the milder form of the disease and according to the original Sillence classification is characterized by minimal skeletal deformities and near‐normal stature. Raman microspectroscopy is a vibrational spectroscopic technique that allows the determination of bone material properties in bone biopsy blocks with a spatial resolution of ～1 µm, as a function of tissue age. In the present study, we used Raman microspectroscopy to evaluate bone material quality in transiliac bone biopsies from children with a mild form of OI, either attributable to collagen haploinsufficiency OI type I (OI‐Quant; n = 11) or aberrant collagen structure (OI‐Qual; n = 5), as a function of tissue age, and compared it against the previously published values established in a cohort of biopsies from healthy children (n = 54, ages 1 to 23 years). The results indicated significant differences in bone material compositional characteristics between OI‐Quant patients and healthy controls, whereas fewer were evident in the OI‐Qual patients. Differences in both subgroups of OI compared with healthy children were evident for nanoporosity, mineral maturity/crystallinity as determined by maxima of the v₁PO₄ Raman band, and pyridinoline (albeit in different direction) content. These alterations in bone material compositional properties most likely contribute to the bone fragility characterizing this disease. © 2016 American Society for Bone and Mineral Research.     

Role of Vitamin D and Parathyroid Hormone in the Regulation of Bone Turnover and Bone Mass in Men: The MINOS Study

We investigated the role of vitamin D and of parathyroid hormone (PTH) in the regulation of bone mineral density (BMD), tone dimensions and seasonal variation of bone turnover in 881 men aged 19–85 years. Bone mineral content (BMC) and BMD of the lumbar spine, hip and whole body were measured with HOLOGIC 1000W and those of distal forearm with an OSTEOMETER DTX 100 device. Bone formation was evaluated using osteocalcin, bone alkaline phosphatase and N-terminal extension propeptide of type I collagen (PINP). Bone resorption was evaluated by 24-hour excretion of deoxypyridinoline and of C-terminal telopeptide of collagen type I. In young men (<55 yrs) PTH level decreased with age (r = –0.18, P < 0.005) whereas 25-hydroxyvitamin D (25OHD) concentration was stable. In older men (>55 years) 25OHD decreased whereas PTH increased with age (r = –0.27 and r = 0.21, P = 0.0001). In young men, 25OHD level varied with season but not PTH, biochemical markers of bone turnover nor BMD. In young men, 25OHD, but not PTH, was a significant determinant of BMC, cortical thickness and of biomechanical properties of the femoral neck. Biochemical bone markers and BMD were not correlated with PTH nor with 25OHD. In elderly men, winter levels of 25OHD were lowest whereas those of PTH, bone resorption markers and PINP were highest. After adjustment for age, body weight and season, biochemical markers of bone turnover were correlated with PTH. In elderly men, 25OHD and PTH were significant determinants of BMC, cortical thickness and of biomechanical parameters of the femoral neck. Men with vertebral deformities had lower concentrations of 25OHD, higher PTH levels and slightly elevated urinary excretion of biochemical markers of bone resorption compared with men without vertebral deformities. In conclusion, in young men, 25OHD discloses a seasonal variability in contrast to PTH and biochemical bone markers. In this group, 25OHD is a significant determinant of BMC and BMD but not of bone size. In elderly men, seasonal variation of 25OHD and PTH concentrations result in seasonal variation of bone resorption. In this group, both 25OHD and PTH are determinants of BMC and cortical thickness of the femoral neck and, consequently, of its mechanical parameters.     

Effects of intravenous pamidronate treatment in infants with osteogenesis imperfecta: clinical and histomorphometric outcome.

Clinical and histomorphometric outcome was compared between children with OI who had received pamidronate since infancy and age-matched patients who had never received pamidronate. Pamidronate was associated with improved vertebral shape and mass, higher cortical width, increased cancellous bone volume, and suppressed bone turnover. INTRODUCTION: Observations in small patient series indicate that infants with severe osteogenesis imperfecta (OI) benefit from treatment with cyclical intravenous pamidronate. However, detailed analyses of outcome are lacking for this age group. MATERIALS AND METHODS: Clinical outcome was evaluated in 29 children with OI types I (n = 3), III (n = 14), or IV (n = 12) who started pamidronate therapy before 2 years of age (age at treatment onset: median, 6 months; range, 2 weeks to 23 months) and who had completed 3 years of treatment (total annual pamidronate dose, 9 mg/kg). They were compared with a historical control group of 29 untreated children with severe OI who were matched for OI type and age at the 3-year treatment time-point. In addition, iliac bone histomorphometry was compared between 24 pamidronate-treated patients and 24 age-matched OI patients who had not received pamidronate. RESULTS: Morphometric evaluation of lumbar vertebrae (L(1)-L(4)) showed that the shape of vertebral bodies was better preserved in pamidronate-treated patients. This was accompanied by significantly higher lumbar spine areal and volumetric BMD (+110 and +96%, respectively) and a larger vertebral bone volume (+26%) on densitometry. Regarding mobility function, the Pediatric Evaluation of Disability Inventory gross motor score was 50% greater in the pamidronate group (p < 0.001). Iliac bone histomorphometry showed 61% higher cortical width and 89% higher cancellous bone volume in pamidronate-treated patients. Bone formation rate per bone surface in the pamidronate group was only 17% that of untreated patients. CONCLUSIONS: In conclusion, this study suggests that cyclical pamidronate treatment started in infancy leads to improved bone strength and better gross motor function but also suppresses bone turnover markedly. It is therefore prudent to reserve pamidronate treatment to infant OI patients who present with a moderate to severe phenotype.     

Bone Health in Children and Adolescents After Renal Transplantation

The basis for lifelong bone health is established in childhood and adolescence. Whereas pediatric renal transplant (RTx) patients are at risk for impaired bone mass gain and fractures, scarce data on this subject are available. We performed a cross‐sectional and longitudinal study of bone health in a national cohort of 106 pediatric RTx patients (median age, 12.6 yr; median follow‐up, 5.1 yr after RTx). The patients underwent clinical evaluation, DXA for BMD, and spinal imaging for vertebral fractures. In longitudinal analysis, the median lumbar spine BMD Z‐score was lowest (median, ?1.0) at 1 yr postoperatively but increased to a peak value of ?0.2 at 5 yr. In boys, the lumbar spine BMD Z‐score increased also during puberty but decreased in girls. In cross‐sectional analysis, the lumbar spine, hip, and whole body BMD Z‐scores were < ?2 SD in 4%, 6%, and 6% of the patients, respectively. Sixteen percent had sustained peripheral fractures, and 8% had vertebral fractures. Female sex and age >15 yr (OR, 56.26; 95% CI, 5.17–611.82; p = 0.0007) as well as high plasma PTH levels (OR, 4.03; 95% CI, 1.37–11.85; p = 0.009) were significant predictors for low BMD. Three‐year cumulative glucocorticoid dose, outside the immediate post‐RTx years, was not associated with BMD parameters. The observed BMD results were satisfactory. However, the high (8%) prevalence of vertebral fractures warrants careful evaluation of bone health in these patients.     

Controlled trial of pamidronate in children with types III and IV osteogenesis imperfecta confirms vertebral gains but not short-term functional improvement.

Bisphosphonates have been widely administered to children with OI based on observational trials. A randomized controlled trial of q3m intravenous pamidronate in children with types III and IV OI yielded positive vertebral changes in DXA and geometry after 1 year of treatment, but no further significant improvement during extended treatment. The treated group did not experience significantly decreased pain or long bone fractures or have increased motor function or muscle strength. INTRODUCTION: Bisphosphonates, antiresorptive drugs for osteoporosis, are widely administered to children with osteogenesis imperfecta (OI). Uncontrolled pamidronate trials in OI reported increased BMD, vertebral coronal area, and mobility, and decreased pain. We conducted a randomized controlled trial of pamidronate in children with types III and IV OI. MATERIALS AND METHODS: This randomized trial included 18 children (4-13 years of age) with types III and IV OI. The first study year was controlled; 9 children received pamidronate (10 mg/m2/day IV for 3 days every 3 months). Four children in each group also received recombinant growth hormone (rGH) injections (0.06 mg/kg/day for 6 days/week). Seven children in the treatment group received pamidronate for an additional 6-21 months. All patients had L1-L4 DXA, spine QCT, spine radiographs, and musculoskeletal and functional testing. RESULTS: In the controlled phase, treated patients experienced a significant increase in L1-L4 DXA z score (p < 0.001) and increased L1-L4 mid-vertebral height (p = 0.014) and total vertebral area (p = 0.003) compared with controls. During extended treatment, DXA z scores and vertebral heights and areas did not increase significantly beyond the 12-month values. Fracture rate decreased significantly in the upper extremities (p = 0.04) but not the lower extremities (p = 0.09) during the first year of treatment. Gross motor function, muscle strength, and pain did not change significantly during the controlled or extended treatment phases. CONCLUSIONS: A controlled trial confirmed the spine benefits of short-term pamidronate treatment in children with types III and IV OI. Pamidronate increased L1-L4 vertebral DXA and decreased vertebral compressions and upper extremity fractures. Vertebral measures did not improve during the extended treatment phase. The treatment group did not experience decreased lower extremity long bone fractures, significant improvement in growth, ambulation, muscle strength, or pain. There was substantial variability in individual response to treatment.     

Differing Lumbar Vertebral Mineralization Rates in Ambulatory Pediatric Patients with Osteogenesis Imperfecta

The purpose of this study was to evaluate serial changes in bone mineral density (BMD) of the lumbar spine in individual children and adolescents with untreated osteogenesis imperfecta (OI) using dual X-ray absorptiometry (DXA). Twenty-seven pediatric patients with OI who had no historical or radiographic evidence of lumbar fracture, required no assistive device for mobility, and were taking no medications known to affect skeletal mineralization during the study period comprised the investigational group. Absolute BMD and age- and gender-matched BMD (Z-scores) were assessed relative to standard parameters of growth (height, weight, age, height adjusted for age and gender and body surface area) and severity of disease (lifetime fracture rate). The spinal mineralization rate (SMR) between examinations for 15 patients with more than one measurement (n= 20 intervals) was expressed as the magnitude of the change in BMD Z-score per year. Both BMD and BMD Z-score were closely correlated with height, height Z-score, weight and body surface area and were inversely related to fracture rate (P < 0.001 for all comparisons). BMD was also highly correlated with patient age (P < 0.001). Stepwise regression analysis showed that together height Z-score and lifetime fracture rate improved the prediction of BMD Z-score (r= 0.71; P < 0.001). SMRs ranged from −0.5 to 3.5. The average change in SMR between sequential measurements was 168% for the five children who had more than two DXA examinations. Linear regression showed a significant negative correlation between SMR and height Z-score (r=−0.79, P < 0.001). We conclude that vertebral body size is a critical determinant of BMD and BMD Z-score in OI because DXA results are expressed per unit area, not per unit volume. Pediatric patients with OI mineralize their lumbar vertebrae at rates similar to healthy children but tend to lag behind in overall mineralization. The rate of mineralization at any age appears to be related to the patient's height (adjusted for age- and gender-matched controls) and inversely related to the patient's lifetime rate of fractures. Our data suggest that vertebral mineralization in children with OI is related primarily to rapid increases in vertebral volume and only secondarily to increases in vertebral mineral density. Received: 2 March 1997 / Accepted: 5 June 1997     

Intravenous pamidronate treatment of children under 36 months of age with osteogenesis imperfecta

INTRODUCTION: Bone mineral density (BMD) and fracture rates in children with osteogenesis imperfecta (OI) have been shown to improve with bisphosphonate therapy. There are limited data available on the efficacy of this therapy in children with OI under the age of 3 years. To examine this, we instituted a prospective clinical trial of intravenous bisphosphonate to study safety, feasibility, and efficacy of this therapy. MATERIALS AND METHODS: Nine infants and young children with osteogenesis imperfecta (age range 1-35 months) were treated with intravenous pamidronate. Six had type II OI, two had type I, and one had type IV. Pamidronate was administered in cycles of 3 consecutive days. The total duration of therapy ranged from 11 to 29 months (mean 17 months). RESULTS: During treatment, the mean annualized percent change in total body areal BMD was 25% (range 11-40%). Pamidronate therapy resulted in sustained and significant decreases in serum calcium and bone-specific alkaline phosphatase and in urine calcium/creatinine and NTX/creatinine. Fracture rate in the group decreased from 80 fractures in 111 months before treatment to 25 fractures in 152 months after treatment (P<0.01). Linear growth and weight gain were maintained. Other than fevers in several infants following the initial dose of intravenous bisphosphonate no adverse effects of therapy were noted. CONCLUSIONS: Our data support that intravenous pamidronate therapy is safe, increases BMD, and reduces fracture rates in very young children with OI. Currently, it would seem to be the best available treatment for these children.     

Bone mineral density and prevalent vertebral fractures in men and women

To test the hypothesis that the association between bone mineral density (BMD) and estimated volumetric BMD and prevalent vertebral fractures differs in men and women, we studied 317 Caucasian men and 2,067 Caucasian women (average age 73 years). A total of 43 (14%) men and 386 (19%) women had a vertebral fracture identified on lateral spine radiographs using vertebral morphometry. Hip and spine areal BMD was about 1/3 standard deviation lower among men and women with a vertebral fracture. A 0.10 g/cm² decrease in areal BMD was associated with 30–40% increased odds of having a fracture in men and 60–70% increased likelihood in women. Low bone mineral apparent density (BMAD) was also associated with 40–50% increased odds of a vertebral fracture in both genders. The probability of a man having a fracture was observed at higher absolute areal BMD values than observed for women (P=values for interaction of BMD × gender: trochanter, P=0.05; femoral neck, P=0.10; total hip, P=0.09). In contrast, the probability of fracture was similar in men and women across the range of estimated volumetric BMD (BMAD). In conclusion, low BMD and low BMAD are associated with increased odds of vertebral fracture in both men and women. Measures of bone mass that partially correct for gender differences in bone size may yield universal estimates of fracture risk. Prospective studies are needed to confirm this observation.     

Accounting for body size deviations when reporting bone mineral density variables in children

Summary  In a child, bone mineral density (BMD) may differ from an age-expected normal value, not only because of the presence of disease, but also because of deviations of height or weight from population averages. Appropriate adjustment for body size deviations simplifies interpretation of BMD measurements. Introduction  For children, a bone mineral density (BMD) measurement is normally expressed as a Z score. Interpretation is complicated when weight or height distinctly differ from age-matched children. We develop a procedure to allow for the influence of body size deviations upon measured BMD. Methods  We examined the relation between body size deviation and spine, hip and whole body BMD deviation in 179 normal children (91 girls). Expressions were developed that allowed derivation of an expected BMD based on age, gender and body size deviation. The difference between measured and expected BMD was expressed as a HAW score (Height-, Age-, Weight-adjusted score). Results  In a second independent sample of 26 normal children (14 girls), measured spine, total femur and whole body BMD all fell within the same single normal range after accounting for age, gender and body size deviations. When traditional Z scores and HAW scores were compared in 154 children, 17.5% showed differences of more than 1 unit and such differences were associated with height and weight deviations. Conclusion  For almost 1 in 5 children, body size deviations influence BMD to an extent that could alter clinical management.     

Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect.

Osteogenesis imperfecta (OI) is a heritable disease of bone in which the hallmark is bone fragility. Usually, the disorder is divided into four groups on clinical grounds. We previously described a group of patients initially classified with OI type IV who had a discrete phenotype including hyperplastic callus formation without evidence of mutations in type I collagen. We called that disease entity OI type V. In this study, we describe another group of 8 patients initially diagnosed with OI type IV who share unique, common characteristics. We propose to name this disorder "OI type VI." Fractures were first documented between 4 and 18 months of age. Patients with OI type VI sustained more frequent fractures than patients with OI type IV. Sclerae were white or faintly blue and dentinogenesis imperfecta was uniformly absent. All patients had vertebral compression fractures. No patients showed radiological signs of rickets. Lumbar spine areal bone mineral density (aBMD) was low and similar to age-matched patients with OI type IV. Serum alkaline phosphatase levels were elevated compared with age-matched patients with type IV OI (409 +/- 145 U/liter vs. 295 +/- 95 U/liter; p < 0.03 by t-test). Other biochemical parameters of bone and mineral metabolism were within the reference range. Mutation screening of the coding regions and exon/intron boundaries of both collagen type I genes did not reveal any mutations, and type I collagen protein analyses were normal. Qualitative histology of iliac crest bone biopsy specimens showed an absence of the birefringent pattern of normal lamellar bone under polarized light, often with a "fish-scale" pattern. Quantitative histomorphometry revealed thin cortices, hyperosteoidosis, and a prolonged mineralization lag time in the presence of a decreased mineral apposition rate. We conclude that type VI OI is a moderate to severe form of brittle bone disease with accumulation of osteoid due to a mineralization defect, in the absence of a disturbance of mineral metabolism. The underlying genetic defect remains to be elucidated.     

Smoking predicts incident fractures in elderly men: Mr OS Sweden

The aim of this study was to investigate the association between smoking and bone mineral density (BMD) and radiographically verified prevalent vertebral fractures and incident fractures in elderly men. At baseline 3003 men aged 69 to 80 years of age from the Swedish Mr Os Study completed a standard questionnaire concerning smoking habits and had BMD of the hip and spine measured using dual‐energy X‐ray absorptiometry (DXA); 1412 men had an X‐ray of the thoracic‐ and lumbar spine. Radiologic registers were used to confirm reported new fractures after the baseline visit. At baseline, 8.4% were current smokers. Current smokers had a 6.2% lower BMD at the total hip and a 5.4% lower BMD at the lumbar spine (p < .001). Current smoking remained independently inversely associated with BMD at the hip and lumbar spine after adjusting for age, height, weight, calcium intake, physical activity, and centers as covariates. Prevalent vertebral fractures among current smokers were increased in unadjusted analyses [odds ratio (OR) = 1.90, 95% confidence interval (CI) 1.26–2.87] and after adjustment for lumbar BMD (OR = 1.67, 95% CI 1.09–2.55). Smokers had a high risk for two or more prevalent vertebral fractures (OR = 3.18, 95% CI 1.88–5.36). During the average follow‐up of 3.3 years, 209 men sustained an X‐ray‐verified fracture. Incident fracture risk among smokers was calculated with Cox proportional hazard models. Current smokers had an increased risk of all new fractures [hazard ratio (HR) = 1.76, 95% CI 1.19–2.61]; nonvertebral osteoporotic fractures, defined as humerus, radius, pelvis, and hip fractures (HR = 2.14, 95% CI 1.18–3.88); clinical and X‐ray‐verified vertebral fractures (HR = 2.53, 95% CI 1.37–4.65); and hip fractures (HR = 3.16, 95% CI 1.44–6.95). After adjustment for BMD, including other covariates, no significant association between smoking and incident fractures was found. Current tobacco smoking in elderly men is associated with low BMD, prevalent vertebral fractures, and incident fractures, especially vertebral and hip fractures. © 2010 American Society for Bone and Mineral Research     

Risedronate decreases fracture risk in patients selected solely on the basis of prior vertebral fracture

The aim of this study was to examine the effects of risedronate (5 mg/daily) in patients identified solely on the basis of a prior fragility fracture, without BMD as an inclusion criterion. A total of 1,802 patients were examined from the VERT-NA and VERT-MN clinical trials. Lateral radiographs (T4 to L4) were obtained at baseline and annually; incident fractures were evaluated using quantitative and semiquantitative methods at the central facility. BMD was measured at the lumbar spine and femoral neck by dual-energy X-ray absorptiometry. Secondary analyses evaluated vertebral fracture efficacy in patient subgroups categorized according to the presence of risk factors for osteoporosis at baseline (age, femoral neck BMD, lumbar spine BMD, more severe BMD, height, weight, body mass index, prevalent nonvertebral fracture status, smoking, and bone turnover marker levels). Over 3 years, risedronate reduced the risk of new vertebral fractures by 44% (95% CI, 28% to 56%) compared with placebo. In patients subgrouped according to the presence or absence of putative risk factors, the efficacy of risedronate was comparable across all groups (all treatment-by-non BMD subgroup interactions p0.210). Adjustment for age, baseline BMD, and prevalent vertebral fractures on fracture risk gave results similar to the unadjusted analysis. In patients taking placebo, the incidence of new vertebral fracture was higher in several of the high-risk categories (elderly, T-score –2.5 SD). In conclusion, the findings of this study suggest that risedronate is effective in patients identified solely on the basis of a prior fragility fracture and that the efficacy of risedronate in the reduction of vertebral fractures is largely independent of the presence of clinical risk factors for osteoporotic fracture.Abbreviations LS Lumbar spine - VERT-MN Vertebral Efficacy with Risedronate Therapy Multinational - VERT-NA Vertebral Efficacy with Risedronate Therapy North American     

High bone mineral density among perimenopausal women

Studies regarding high bone mineral density (HBMD) are few. In the population-based Kuopio Osteoporosis Risk Factor and Prevention Study, BMDs of women were measured from 1990–1991 and 1995–1997. The mean age of the 1,873 women studied was 53.5 years at baseline (range 48.0–59.6). In all, 248 women were excluded because of BMD measurement errors or artifacts: 41 from the HBMD group (20.6%) and 207 (12.4%) from the control group. The final study group consisted of 1,551 women, 168 in the HBMD group (baseline lumbar BMD >1.23 g/cm²; femoral BMD >1.01 g/cm², and 5-year follow-up lumbar BMD >1.21 g/cm²; femoral BMD >0.98 g/cm², respectively) and 1,383 in the control group. The predictors for HBMD in the multivariate regression analysis were as follows: hormone therapy (HT) during the follow-up from 0.5 to 2 years and for over 2 years (OR 2.06, CI: 1.11–3.81 and OR 2.16, CI 1.43–3.26) and being overweight (BMI from 25 kg/m² to 30 kg/m², and BMI >30 kg/m²) at baseline (OR 2.84, CI: 1.82–4.42; OR 5.94, CI: 3.47–10.16, respectively). High physical activity while 11–18 years of age was associated with HBMD (OR 1.69, CI: 1.17–2.45). Parity predicted HBMD so that after one to two births the OR was 2.66 (CI: 1.03–6.88) and 3.03 (CI: 1.16–7.90) after three or more births. Menopause was negatively associated with HBMD (OR 0.57, CI 0.38–0.85). There were more premenopausal women in the HBMD group (53.9 vs. 34.6%, P <0.001). The HBMD group showed fewer fractures. In conclusion, being overweight, parity, HT use, premenopause and high physical activity in adolescence seemed to be predictors for persistently high BMD in early postmenopausal women. We suggest that the fracture risk is low in these women, and thus they are neither primary candidates for BMD screening nor for osteoporosis medication.     

A roadmap to surgery in osteogenesis imperfecta: results of an international collaboration of patient organizations and interdisciplinary care teams

Background and purpose — Involvement of patient organizations is steadily increasing in guidelines for treatment of various diseases and conditions for better care from the patient’s viewpoint and better comparability of outcomes. For this reason, the Osteogenesis Imperfecta Federation Europe and the Care4BrittleBones Foundation convened an interdisciplinary task force of 3 members from patient organizations and 12 healthcare professionals from recognized centers for interdisciplinary care for children and adults with osteogenesis imperfecta (OI) to develop guidelines for a basic roadmap to surgery in OI.Methods — All information from 9 telephone conferences, expert consultations, and face-to-face meetings during the International Conference for Quality of Life for Osteogenesis Imperfecta 2019 was used by the task force to define themes and associated recommendations.Results — Consensus on recommendations was reached within 4 themes: the interdisciplinary approach, the surgical decision-making conversation, surgical technique guidelines for OI, and the feedback loop after surgery.Interpretation — The basic guidelines of this roadmap for the interdisciplinary approach to surgical care in children and adults with OI is expected to improve standardization of clinical practice and comparability of outcomes across treatment centers.

Expert consensus remains the best available method for guiding surgical care in most rare diseases, due to the relative lack of evidence-based practices. With a prevalence between 1:10,000 and 1:20,000, osteogenesis imperfecta (OI) is a rare genetic disease affecting the quality and quantity of collagen I. Not only bone with frequent fractures and deformities, but all tissues containing collagen I are affected (Marini et al. 2017, Chougui et al. 2020). The somewhat unpredictable phenotypic variability of the disease is often grouped according to the clinical Sillence classification I–V (Van Dijk and Sillence 2014). However, each patient is unique not only in impairments but also in treatment needs. The most severe type III has the weakest bone and not all these individuals reach the level of standing and walking. Many patients undergo surgery more than once. On the initiative of the Osteogenesis Imperfecta Federation Europe (OIFE) and the Care4BrittleBones (Care4BB) Foundation, an international interdisciplinary task force was invited to create a roadmap for a standardized, integrated approach for optimal outcomes of surgery, not only from a surgical view, but also from the patient’s perspective.     

Type V osteogenesis imperfecta: a new form of brittle bone disease.

Osteogenesis imperfecta (OI) is commonly subdivided into four clinical types. Among these, OI type IV clearly represents a heterogeneous group of disorders. Here we describe 7 OI patients (3 girls), who would typically be classified as having OI type IV but who can be distinguished from other type IV patients. We propose to call this disease entity OI type V. These children had a history of moderate to severe increased fragility of long bones and vertebral bodies. Four patients had experienced at least one episode of hyperplastic callus formation. The family history was positive for OI in 3 patients, with an autosomal dominant pattern of inheritance. All type V patients had limitations in the range of pronation/supination in one or both forearms, associated with a radiologically apparent calcification of the interosseous membrane. Three patients had anterior dislocation of the radial head. A radiodense metaphyseal band immediately adjacent to the growth plate was a constant feature in growing patients. Lumbar spine bone mineral density was low and similar to age-matched patients with OI type IV. None of the type V patients presented blue sclerae or dentinogenesis imperfecta, but ligamentous laxity was similar to that in patients with OI type IV. Levels of biochemical markers of bone metabolism generally were within the reference range, but serum alkaline phosphatase and urinary collagen type I N-telopeptide excretion increased markedly during periods of active hyperplastic callus formation. Qualitative histology of iliac biopsy specimens showed that lamellae were arranged in an irregular fashion or had a meshlike appearance. Quantitative histomorphometry revealed decreased amounts of cortical and cancellous bone, like in OI type IV. However, in contrast to OI type IV, parameters that reflect remodeling activation on cancellous bone were mostly normal in OI type V, while parameters reflecting bone formation processes in individual remodeling sites were clearly decreased. Mutation screening of the coding regions and exon/intron boundaries of both collagen type I genes did not reveal any mutations affecting glycine codons or splice sites. In conclusion, OI type V is a new form of autosomal dominant OI, which does not appear to be associated with collagen type I mutations. The genetic defect underlying this disease remains to be elucidated.