Stefano Gonnelli

Quantitative Ultrasound in the Management of Osteoporosis: The 2007 ISCD Official Positions

Dual-energy X-ray absorptiometry (DXA) is commonly used in the care of patients for diagnostic classification of osteoporosis, low bone mass (osteopenia), or normal bone density; assessment of fracture risk; and monitoring changes in bone density over time. The development of other technologies for the evaluation of skeletal health has been associated with uncertainties regarding their applications in clinical practice. Quantitative ultrasound (QUS), a technology for measuring properties of bone at peripheral skeletal sites, is more portable and less expensive than DXA, without the use of ionizing radiation. The proliferation of QUS devices that are technologically diverse, measuring and reporting variable bone parameters in different ways, examining different skeletal sites, and having differing levels of validating data for association with DXA-measured bone density and fracture risk, has created many challenges in applying QUS for use in clinical practice. The International Society for Clinical Densitometry (ISCD) 2007 Position Development Conference (PDC) addressed clinical applications of QUS for fracture risk assessment, diagnosis of osteoporosis, treatment initiation, monitoring of treatment, and quality assurance/quality control. The ISCD Official Positions on QUS resulting from this PDC, the rationale for their establishment, and recommendations for further study are presented here.

Phalangeal Osteosonogrammetry Study: Age‐Related Changes, Diagnostic Sensitivity, and Discrimination Power

Phalangeal osteosonogrammetry was introduced as a method for bone tissue investigation in 1992. It is based on the measure of the velocity of ultrasound (amplitude‐dependent speed of sound [AD‐SoS]) and on the interpretation of the characteristics of the ultrasound signal. In this study we have collected a database of 10,115 subjects to evaluate the performance of AD‐SoS and to develop a parameter that is able to quantify the signal characteristics: ultrasound bone profile index (UBPI). The database only includes females of which 4.5% had documented vertebral osteoporotic fractures, 16% lumbar spine dual X‐ray absorptiometry (DXA), and 6% hip DXA. The analysis of the ultrasound signal has shown that with aging the UBPI, first wave amplitude (FWA), and signal dynamics (SDy) follow a trend that is different from the one observed for AD‐SoS; that is, there is no increase during childhood. In the whole population, the risk of fracture per SD decrease for AD‐SOS was odds ratio (OR) 1.71 (CI, 1.58‐1.84). The AD‐SoS in fractured subjects was significantly lower than in a group of age‐matched nonfractured subjects (p < 0.0001). In a small cohort of hip‐fractured patients UBPI proved to be lower than in a control age‐matched group (p < 0.0001). When the World Health Organization (WHO) working group criteria were applied to this population to identify the T score value for osteoporosis, for AD‐SoS we found a T score of −3.2 and for UBPI we found a T score of −3.14. Sixty‐six percent of vertebral fractures were below the AD‐SoS −3.2 T score and 62% were below UBPI −3.14. We observed the highest incidence of fractures (63.6%) among subjects with AD‐SoS who had both DXA T score values below the threshold. We conclude from this study that ultrasound investigation at the hand phalanges is a valid methodology for osteoporosis assessment. It has been possible to quantify signal changes by means of UBPI, a parameter that will improve the possibility of investigating bone structure.

Effects of salmon calcitonin in postmenopausal osteoporosis: A controlled double-blind clinical study

SummaryIn this paper we present the results of a 12-month double-blind clinical multicenter study assessing the effects of synthetic salmon cacitonin (CT) administration in a group of white postmenopausal osteoporotic women. Treated patients were given 100 MRC units of synthetic salmon CT injected i.m. in the morning every other day. Control patients received a placebo injection. All patients received 500 mg of elementary calcium p.o., b.i.d. Bone mineral content (BMC) was measured at the extreme distal radius of the nondominant arm by a dual photon bone densitometer which utilizes two radionuclides,241Am and125I, with energies of about 60 keV and 30 keV respectively. Biochemical parameters of calcium-phosphorus metabolism were also measured. After 12 months of treatment a significant mean increment of BMC and nondialyzable OHPr/creatinine values and a significant decrease of total OHPr/creatinine values were observed in the treated group, while controls showed a significant decrease in BMC values. These results, together with the observation that in some patients the decrease in total OHPr/creatinine values was not accompanied by an increment of BMC, show that long-term salmon CT treatment may be of benefit in postmenopausal osteoporosis and that the effects of CT on bone mass may be due not only to the inhibition of bone resorption but also to the stimulation of bone formation.

Effect of simvastatin treatment on bone mineral density and bone turnover in hypercholesterolemic postmenopausal women: a 1-year longitudinal study

Although several studies have reported a lower risk of osteoporotic fracture in hypercholesterolemic patients treated with statins, so far longitudinal studies on the effects of statins on bone are lacking. The aim of the present study was to evaluate bone mineral density (BMD) and bone turnover changes induced by 1-year simvastatin treatment on postmenopausal women. Thirty consecutive postmenopausal hypercholesterolemic women (61.2 +/- 4.9 years) were treated for 12 months with 40 mg/day simvastatin and 30 normocholesterolemic age-matched postmenopausal women provided control data. In all subjects, at baseline and at 3-month intervals, serum lipids, calcium, phosphate, total and bone alkaline phosphatase (Bone-ALP), and carboxy-terminal fragment of type I collagen (CTx) were measured in a fasting blood sample. At baseline and after 6 and 12 months BMD was measured at lumbar spine (BMD-LS) and at femur (BMD-Ftot) and at femoral neck (BMD-Fn) by DXA. In the simvastatin-treated group Bone-ALP showed a significant increase (P < 0.05) with respect to baseline from the sixth month, whereas serum CTx showed a weak and nonsignificant increase over the study period. In treated women BMD-LS, BMD-Fn, and BMD-Ftot increased respectively by 1.1, 0.9, and 0.4% at Month 6; and by 2.8, 1.0, and 0.8% at Month 12. In controls BMD-LS, BMD-Fn, and BMD-Ftot at the end of the study period decreased by 1.6, 1.4, and 1.2%, respectively. The difference between controls and simvastatin-treated patients was significant (P < 0.05) for both BMD-LS and BMD-Fn only at Month 12. In conclusion our results, although obtained from a small sample of postmenopausal hypercholesterolemic women, suggest a probable positive effect of simvastatin on bone formation and BMD.

Prevention of corticosteroid-induced osteoporosis with alendronate in sarcoid patients.

Abstract. Prolonged corticosteroid administration, as often required in the treatment of sarcoidosis, increases the risk of osteoporosis and fracture. The aim of the present study was to evaluate the usefulness of alendronate, a third generation bisphosphonate, in preventing corticosteroid-induced osteoporosis. Forty-three consecutive, previously untreated, sarcoid patients (17 men and 26 premenopausal women) were included in the study: 13 needed no treatment and served as controls (Group 1) and 30 needed glucocorticoids (prednisone) and were randomly selected to also receive either placebo (n = 15, Group 2) or alendronate 5 mg/day (n = 15, Group 3). Bone mineral density (BMD) at the ultradistal radius by dual photon absorptiometry (Osteograph 1000, NIM, Verona, Italy) and biochemical markers of bone turnover were measured at baseline and after 6 and 12 months of glucocorticoid therapy. No significant difference was found between Groups 2 and 3 in the mean cumulative dose of prednisone (4945 ± 1956 mg and 5110 ± 2013 mg, respectively). At the end of the study period, BMD increased by 0.8% in the alendronate-treated group; in the placebo-treated group, BMD decreased by 4.5%. The difference between groups was significant (P < 0.01, ANOVA). A significant decrease in markers of bone formation was found in all patients treated with prednisone (Groups 2 and 3), independently of alendronate. Alendronate, however, counteracted the increase in markers of bone resorption induced by glucocorticoid therapy. Our data suggest that alendronate is effective in preventing glucocorticoid-induced bone loss in sarcoid patients. Further studies on alendronate use in steroid-induced osteoporosis are needed.

FokI Polymorphism at Translation Initiation Site of the Vitamin D Receptor Gene Predicts Bone Mineral Density and Vertebral Fractures in Postmenopausal Italian Women

A novel T/C polymorphism (ATG to ACG) at the translation initiation site of the vitamin D receptor (VDR) gene, defined by FokI restriction endonuclease, has been recently associated with variation in bone mineral density (BMD) and rates of bone loss in a group of postmenopausal Mexican‐American women. The presence of the restriction site, designated as f, allows protein translation to initiate from the first ATG, while the allele lacking the site, indicated as F, initiates translation at a second ATG. In this study, we investigated the role of FokI polymorphism in a group of 400 postmenopausal women of Italian descent stratified for BMD into osteoporotic (n = 164), osteopenic (n = 117), and normal (n = 119) groups. There were 159 (41%) FF homozygotes, 55 (14%) ff homozygotes, and 186 (45%) Ff heterozygotes. In the whole population, we observed a weak association between FokI polymorphism and lumbar BMD (p = 0.06, analysis of covariance [ANCOVA]) but not with femoral neck BMD (p = 0.5, ANCOVA). Interestingly, the effect of FokI genotypes on lumbar BMD was influenced by the years since menopause such that differences in BMD related to different VDR allelic variants were greater among women in the first 5 years of menopause (p = 0.04, ANCOVA), progressively declining afterward. In addition, a significantly higher prevalence of ff genotype in osteoporotic than in osteopenic and normal women was observed (p = 0.04, Chi‐square test). Finally, ff genotype resulted significantly over‐represented in the group of women with a vertebral fracture as compared with controls (p = 0.003, Chi‐square test), equivalent to a relative risk of 2.58 (95% confidence intervals 1.36–4.91). We conclude that in this population, FokI polymorphism at the VDR gene locus accounts for a part of the heritable component of BMD at the lumbar spine.

Diagnostic value of ultrasound analysis and bone densitometry as predictors of vertebral deformity in postmenopausal women

Bone fractures depend not only on bone density, but also on bone quality. Ultrasound (US) has been proposed as a technique for evaluating skeletal status. Speed of sound (SOS) and broadband ultrasound attenuation (BUA) are the US properties currently used to assess bone strength and fragility. In 304 postmenopausal women (age 58.8±5.5 years) we measured: bone mineral density (BMD) of the lumbar spine (by dual-energy X-ray absorptiometry), SOS, BUA and Stiffness in the os calcis (using an Achilles machine). In all subjects we performed lateral lumbar and thoracic radiographs. Morphometric parameters were derived by measuring the anterior, middle and posterior height of each vertebral body, to obtain a semiquantitative grading of vertebral fractures as follows: 0, no vertebral deformity; 1, any vertebral height reduced between 20% and 25%; 2, any vertebral height reduced between 25% and 40%; 3, any vertebral height reduced more than 40%. On the basis of the number and severity of vertebral deformities the women were divided into: group 1 (n=79), normal; group 2(n=80), mild; group 3 (n=85), moderate; and group 4 (n=60), severe. Mean values of SOS, BUA, Stiffness and BMD were significantly lower (p<0.001) in women with vertebral deformity than in normals. In the whole population SOS, BUA and Stiffness values were significantly correlated with BMD. SOS, BUA and Stiffness values were significantly decreased (p<0.001) with vertebral deformity, as was BMD. Receiver operating characteristic (ROC) curve analysis showed BMD to be slightly better than Stiffness in discriminating among groups. Logistic regression analysis showed that BMD, BUA, SOS and Stiffness were independent predictors of vertebral fracture risk. Ultrasound parameters were still significant independent predictors of vertebral fracture even after adjusting for BMD.

Alendronate Treatment in Men With Primary Osteoporosis: A Three-Year Longitudinal Study

Bisphosphonates have been widely used in the treatment of osteoporosis in women, whereas until now there have been few data on their use in men. The aim of this study was to evaluate the effect of a 3-year alendronate treatment on bone mineral density (BMD) and quantitative ultrasound (QUS) in men with primary osteoporosis. We studied 77 osteoporotic men (aged 57.1 ± 10.8 yrs) who completed a 3-year treatment with alendronate (10 mg/day) plus calcium (1000 mg/day) (n = 39), or calcium alone (n = 38). At baseline and at a 12-month interval, we measured BMD at the lumbar spine and femur (femoral neck and total hip) by DXA (Hologic) and speed of sound (SOS), broadband ultrasound attenuation (BUA) and Stiffness (S) at the os calcis by Achilles plus (Lunar). Alendronate treatment had significantly increased lumbar spine BMD by 4.2% at year 1, by 6.3% at year 2, and 8.8% at year 3. BMD at the femoral neck and total hip had increased by 2.1% and 1.6% at year 1, by 3.2% and 2.9% at year 2, and by 4.2% and 3.9% at year 3, respectively. BUA and Stiffness showed a significant increase in the alendronate-treated group at year 2 (3.2% and 4.9%, respectively) and at year 3 (3.8% and 6%, respectively). BMD at the lumbar spine showed the best longitudinal sensitivity whereas longitudinal sensitivity of both QUS at the heel and femur BMD were similar. In conclusion, this study confirms that alendronate represents an important therapeutic advance in the management of male osteoporosis. BMD at the lumbar spine appears to be the best method for monitoring the effect of alendronate on bone mass in osteoporotic men.

Quantitative ultrasound and dual-energy X-ray absorptiometry in the prediction of fragility fracture in men

Fragility fractures in men represent a major health problem, and this prompts a necessity for reliable tools for the identification of men at risk of fracture. In order to assess the ability of dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS) in the prediction of fracture risk in men and whether their combination might be useful in a clinical setting, we studied 401 men (age range 45–82 years, mean 60.3±12.5), of whom 133 had osteoporotic fractures and 268 did not. In all subjects we measured bone mineral density at the lumbar spine (BMD-LS) and at the femur, calculating thereafter the standard femoral subregions: neck (BMD-FN), total hip (BMD-T), trochanter (BMD-TR), intertrochanter (BMD-ITR), and Ward’s triangle (BMD-W), by DXA. We also performed ultrasound parameters at the calcaneus: speed of sound (SOS), broadband ultrasound attenuation (BUA) and Stiffness, by Achilles plus, and at the phalanxes: amplitude dependent speed of sound (AD-SoS) and the parameters of the graphic trace: bone transmission time (BTT), fast wave amplitude (FWA), signal dynamic (SDy) and ultrasound bone profile index (UBPI), by Bone Profiler. All DXA and QUS parameters, apart from FWA, were significantly (P<0.001) lower in patients with a history of fracture. BMD at the proximal femur showed the best ability in discriminating men with or without fractures. QUS at the heel showed discriminatory ability significantly better than QUS at the fingers. By logistic regression analysis, adjusted for age and BMI, BMD-T showed the best association with fragility fracture [odds ratio (OR)=3.43, 95% confidence interval (CI)=2.47–4.77]. Among QUS parameters, the highest value of the OR was shown by stiffness (OR=3.18, CI=2.27–4.48). FWA and SDy were not associated with fragility fractures in men. If DXA and QUS were combined, the prediction of the OR of fragility fracture events in men increases; in fact Stiffness was able to increase the OR when added to BMD-LS (OR=5.44, CI=3.16–10.13) and BMD-T (OR=6.08, CI=2.63–14.27). SOS and BUA showed a similar pattern. AD-SoS improved the prediction of fracture only when combined with BMD-LS (OR=4.36, CI=1.99–9.57). If BMD-LS and BMD-FN or BMD-T were combined, the value of the OR increases (OR=4.59, CI=2.27–9.25 and OR=4.68, CI=2.24–9.76), respectively. Our study supports the effectiveness of QUS in the identification of osteoporotic fractures in men. QUS seems to play an independent and complementary role, with respect to DXA, in order to enhance the power for predicting osteoporotic fractures in men.

An effective regimen of intranasal salmon calcitonin in early postmenopausal bone loss

SummaryIn order to devise a convenient and effective therapeutic regimen of intranasal salmon calcitonin (sCT) for the treatment of early postmenopausal bone loss, we studied the effects of a 1-year course of sCT nasal spray on vertebral mineral content (VMC), assessed by dual photon densitometry, and bone turnover in 21 early postmenopausal osteoporotic women. Subjects enrolled in the study had a value above the normal average of at least one index of bone turnover: whole body retention (WBR) of 99mTc-methylenedichloro-bisphosphonate (99mTc-MDP), serum bone gla protein (BGP), urinary hydroxyproline/creatinine excretion (HOP/Cr). After baseline evaluation, patients were randomized for treatment with either sCT (200 IU every other day) or plabebo. Treatment with sCT significantly increased VMC by 2.7±0.9% at 6 months, and 3.3±0.8% at 1 year, whereas a progressive decline was observed in the placebo group (-2.6±0.5%, and -3.5±0.5% after 6 and 12 months, respectively). These changes were associated with a progressive and significant reduction of all parameters of bone turnover in the sCT-treated patients, whereas no changes were detected in the control group during the study period. The differences between the two groups were significant after 1 year for VMC, BGP, and WBR (P<0.05, one-way analysis of variance). Thus, 200 IU intranasal sCT administered on alternate days is adequate to stop the fast bone loss occurring early after the menopause in women with high bone turnover rates. This therapeutical modality represents an important addition to the available pharmacologic spectrum for the prevention and treatment of postmenopausal osteoporosis.