Maurizio Rossini

Obesity is not protective against fracture in postmenopausal women: GLOW

OBJECTIVE To investigate the prevalence and incidence of clinical fractures in obese, postmenopausal women enrolled in the Global Longitudinal study of Osteoporosis in Women (GLOW). METHODS This was a multinational, prospective, observational, population-based study carried out by 723 physician practices at 17 sites in 10 countries. A total of 60,393 women aged ≥ 55 years were included. Data were collected using self-administered questionnaires that covered domains that included patient characteristics, fracture history, risk factors for fracture, and anti-osteoporosis medications. RESULTS Body mass index (BMI) and fracture history were available at baseline and at 1 and 2 years in 44,534 women, 23.4% of whom were obese (BMI ≥ 30 kg/m(2)). Fracture prevalence in obese women at baseline was 222 per 1000 and incidence at 2 years was 61.7 per 1000, similar to rates in nonobese women (227 and 66.0 per 1000, respectively). Fractures in obese women accounted for 23% and 22% of all previous and incident fractures, respectively. The risk of incident ankle and upper leg fractures was significantly higher in obese than in nonobese women, while the risk of wrist fracture was significantly lower. Obese women with fracture were more likely to have experienced early menopause and to report 2 or more falls in the past year. Self-reported asthma, emphysema, and type 1 diabetes were all significantly more common in obese than nonobese women with incident fracture. At 2 years, 27% of obese women with incident fracture were receiving bone protective therapy, compared with 41% of nonobese and 57% of underweight women. CONCLUSIONS Our results demonstrate that obesity is not protective against fracture in postmenopausal women and is associated with increased risk of ankle and upper leg fractures.

Determinants of adherence to osteoporosis treatment in clinical practice

IntroductionPoor adherence to prescribed treatments is widespread in clinical practice and this can lead to potentially life-threatening events. This problem is apparently very common for osteoporosis treatment but the causes of discontinuation and low compliance are complex and poorly defined.MethodsGlobal adherence to osteoporosis treatment was specifically addressed in a nation-wide survey carried out in 9851 postmenopausal women referred to 141 Italian centres for osteoporosis management for a follow-up assessment, at least one year after having been prescribed a treatment with one of the following drugs: calcium±vitamin D supplements alone (CaVitD), hormone replacement therapy (HRT), raloxifene 60 mg (RLX), intramuscular clodronate 100 mg/7-14 days (CLOD), risedronate 5 mg/day (RIS) and alendronate 10mg/daily (ALN10) or 70 mg once weekly (ALN OW).ResultsOverall 19.1% of the patients discontinued the prescribed drug before attending the bone mass re-evaluations, more than half of them within the first 6 months. The discontinuation rate was significantly different between the treatments. The medications most frequently interrupted within one year were CLOD (28.7%; p<0.01 versus any other treatment), while by far the least interrupted was ALN-OW (6.9%; p<0.001 versus any other treatment). The most frequent reasons for discontinuation were drug related side effects, insufficient motivation to treatment and fear of side effects. The prevalence of the reasons for discontinuation were different among treatments: safety concerns were very common for HRT, lack of motivation was the most common cause for CaVitD and CLOD, and drug related side effects for RIS, ALN and RLX. Persistence to treatment was significantly higher in patients with previous vertebral fractures, densitometric osteoporosis, on corticosteroid or anti-inflammatory treatments. A significantly increased risk of treatment interruption was found among patients on benzodiazepine or gastro-protective agents and in patients in whom a bone measurement was not readily available. The highest compliance to recommended dosing was observed with ALN OW and HRT (p<0.001 versus any other) and the lowest for CaVitD (p<0.01 versus any other). Poor treatment compliance (<50% drug taken) was significantly related to benzodiazepine and gastroprotective use, while a significantly better compliance was associated with recognized risk factors for osteoporosis: early menopause, low bone mass values values, previous vertebral fractures. The poorest adherence was observed when treatments were prescribed by General practitioners (GPs), and orthopaedic surgeons (p<0.01 versus global mean).ConclusionsThe results of this large survey of Italian osteoporotic women indicates that the most important determinant of both persistence and compliance to treatment is the type of drug prescribed with a definite advantage of ALN-OW. Treatment compliance is particularly poor for CaVitD and this emphasizes the need for new ways to supplement at least vitamin D. The main reasons for discontinuation are side effects and lack of motivation while the best treatment adherence was observed in patients with severe and well documented osteoporosis.

Intravenous neridronate in children with osteogenesis imperfecta: a randomized controlled study.

In a randomized controlled study, we investigated the effect of treatment with intravenous neridronate in prepubertal children with OI. Our study suggests that quarterly intravenous infusions of the bisphosphonate significantly raise the rate of increase in BMD at both the spine and hip, the projected area of the lumbar vertebrae, and height. These results are associated with a significant decrease in the risk of clinical fractures.

Site‐Specific Effects of Strength Training on Bone Structure and Geometry of Ultradistal Radius in Postmenopausal Women

Knowledge of the effects of exercise on bone mass in postmenopausal women is limited and controversial. Animal studies have shown that the response of bone to bending strain is an alteration of bone geometry. We studied 250 postmenopausal women, aged 52–72 years, willing to participate in a 6‐month exercise program. The first 125 started the program immediately and the remaining 125 served as controls. The training program included exercises designed to maximize the stress on the wrist. One hundred and eighteen of the active group and 116 of the control group completed the study and were reassessed 6 months later. Bone mineral density (BMD) of the femoral neck, lumbar spine, ultradistal and proximal radius was measured by dual‐energy X‐ray absorptiometry (DXA) both before and at the end of the exercise program. The forearm was also evaluated by peripheral quantitative computed tomography, which measures the area, bone mineral content (BMC), and volumetric density for both the cortical and the trabecular component. The results showed that the DXA measurements at the femoral neck, lumbar spine, ultradistal and proximal radius were similar between the two groups. No significant difference was detected after the exercise program at the proximal radius. At the ultradistal radius, the cross‐sectional area of cortical bone rose by 2.8 ± 15.0% (SD, p < 0.05), apparently for both periosteal apposition and corticalization of the trabecular tissue. The volumetric density of cortical bone rose by 2.2 ± 15.8% (p < 0.1), and that of trabecular bone decreased by 2.6 ± 10.7% (p < 0.01). The combined changes in both bone volume and density in the exercise group were associated with marked increase in cortical BMC (3.1 ± 10.7%, p < 0.01) and decrease in trabecular BMC (−3.4 ± 14.2%, p < 0.05), which were statistically different from those observed in the control group (p < 0.05). In conclusion, these results confirm that site‐specific moderate physical exercises have very little effect on bone mass. However, it appears that some exercises may reshape the bone segment under stress by increasing both the cross‐sectional area and the density of the cortical component. These structural changes are theoretically associated with increases in the bending strength.

Effects of Oral Alendronate in Elderly Patients with Osteoporosis and Mild Primary Hyperparathyroidism

In a large proportion of the patients with primary hyperparathyroidism (PHPT), a variable degree of osteopenia is the only relevant manifestation of the disease. Low bone mineral density (BMD) in patients with PHPT is an indication for surgical intervention because successful parathyroidectomy results in a dramatic increase in BMD. However, low BMD values are almost an invariable finding in elderly women with PHPT, who are often either unwilling or considered unfit for surgery. Bisphosphonates are capable of suppressing parathyroid hormone (PTH)‐mediated bone resorption and are useful for the prevention and treatment of postmenopausal osteoporosis. In this pilot‐controlled study, we investigated the effects of oral treatment with alendronate on BMD and biochemical markers of calcium and bone metabolism in elderly women presenting osteoporosis and mild PHPT. Twenty‐six elderly patients aged 67–81 years were randomized for treatment with either oral 10 mg alendronate on alternate‐day treatment or no treatment for 2 years. In the control untreated patients a slight significant decrease was observed for total body and femoral neck BMD, without significant changes in biochemical markers of calcium and bone metabolism during the 2 years of observation. Urine deoxypyridinoline (Dpyr) excretion significantly fell within the first month of treatment with alendronate, while serum markers of bone formation alkaline phosphatase and osteocalcin fell more gradually and the decrease became significant only after 3 months of treatment; thereafter all bone turnover markers remained consistently suppressed during alendronate treatment. After 2 years in this group we observed statistically significant increases in BMD at lumbar spine, total hip, and total body (+8.6 ± 3.0%, +4.8 ± 3.9%, and +1.2 ± 1.4% changes vs. baseline mean ± SD) versus both baseline and control patients. Serum calcium, serum phosphate, and urinary calcium excretion significantly decreased during the first 3‐6 months but rose back to the baseline values afterward. Increase in serum PTH level was statistically significant during the first year of treatment. These preliminary results may make alendronate a candidate as a supportive therapy in patients with mild PHPT who are unwilling or are unsuitable for surgery, and for whom osteoporosis is a reason of concern.

Fat-free mass and fat mass reference values by dual-energy X-ray absorptiometry (DEXA) in a 20–80 year-old Italian population

BACKGROUND & AIMS To establish reference values for limb composition, fat-free mass (FFM) and fat mass (FM) in Italian adults for gender-specific age brackets 20-80 years old and to assess age-related regional changes in body composition. METHODS A multicenter, retrospective study was conducted on 1571 healthy subjects, 1240 women and 331 men. Regional FFM and FM were measured by dual-energy X-ray absorptiometry. FM was expressed as % of limb weight. RESULTS FFM in men diminished with age in both arms and legs, with reference ranges (25th -75th percentile) of 3.8-4.6 kg and 10.4-12.2 kg, respectively for 20-29 year-olds, and 3.1-3.9 kg and 8.2-10.4 kg for 70-79 year-olds. Womens arm FFM remained stable with aging (reference values 1.7-2.2 kg), decreasing in their legs (6.2-7.2 kg for 20-29 year-olds, 5.5-6.5 kg for 70-79 year-olds). Limb FM% increased with age in both genders: the reference values were 9-15% (arms) and 12-21% (legs) for 20-29 year-old men, and 19-26% and 19-29%, respectively, for 70-79 year-olds; for womens arms, they were 25-36% for 20-29 year-olds and 36-48% for 70-79 year-olds, while their leg FM remained the same with aging, i.e. 32-40%. CONCLUSIONS These data complete the published reference values for whole body composition, enabling physiological or pathological changes in limb composition to be identified in Caucasian populations living in the Mediterranean area.

Relationship Between Lipids and Bone Mass in 2 Cohorts of Healthy Women and Men

A number of recent findings seem to indicate that fat and bone metabolism are strictly connected. We investigated the relationship between lipid profile and bone mineral density (BMD) in 236 either pre- or postmenopausal women, aged 35–81 years, attending our osteoporosis center (“clinic group”). In order to verify the consistency of the results, 265 men and 481 women aged 68–75, participating in a population-based epidemiological investigation (“community cohort”), were also studied. Lumbar spine, femoral neck, total hip and total body BMD, total body fat, % fat mass and lean mass were measured using dual energy X-ray absorptiometry (DXA). In the clinic group, lumbar spine and hip BMD Z score values were both strongly related to all measured serum lipids: the relationship was negative for HDL cholesterol (P < 0.05) and Apo A lipoprotein (P < 0.000) and positive for LDL cholesterol (P < 0.05), Apo B lipoprotein (P < 0.001) and triglycerides (P < 0.05). When BMD values were adjusted for body weight and BMI, most relationships remained statistically significant. In the community cohort, total body and hip BMD values were strongly related in both men and women to age, body weight, height, BMI, fat mass, lean mass, % fat mass. Total body and hip BMD were significantly related to serum lipids in both women and men. The relationship was negative for HDL cholesterol and positive for total cholesterol, triglycerides and LDL cholesterol. Most of these relationships (triglycerides, HDL cholesterol, LDL/HDL cholesterol ratio in women, and all measured lipids in men) remained statistically significant (P values ranging from 0.000 to 0.03) when the BMD values were adjusted also for anthropometric measures (body weight, height, fat mass). This study demonstrates for the first time that the lipid profile is strictly related to bone mass in both men and women. The interpretation of this association remains hypothetical but it might open new perspectives for understanding the mechanisms controlling bone metabolism.

Relationship of Weight, Height, and Body Mass Index with Fracture Risk at Different Sites in Postmenopausal Women: The Global Longitudinal study of Osteoporosis in Women (GLOW)

Low body mass index (BMI) is a well‐established risk factor for fracture in postmenopausal women. Height and obesity have also been associated with increased fracture risk at some sites. We investigated the relationships of weight, BMI, and height with incident clinical fracture in a practice‐based cohort of postmenopausal women participating in the Global Longitudinal study of Osteoporosis in Women (GLOW). Data were collected at baseline and at 1, 2, and 3 years. For hip, spine, wrist, pelvis, rib, upper arm/shoulder, clavicle, ankle, lower leg, and upper leg fractures, we modeled the time to incident self‐reported fracture over a 3‐year period using the Cox proportional hazards model and fitted the best linear or nonlinear models containing height, weight, and BMI. Of 52,939 women, 3628 (6.9%) reported an incident clinical fracture during the 3‐year follow‐up period. Linear BMI showed a significant inverse association with hip, clinical spine, and wrist fractures: adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) per increase of 5 kg/m2 were 0.80 (0.71–0.90), 0.83 (0.76–0.92), and 0.88 (0.83–0.94), respectively (all p < 0.001). For ankle fractures, linear weight showed a significant positive association: adjusted HR per 5‐kg increase 1.05 (1.02–1.07) (p < 0.001). For upper arm/shoulder and clavicle fractures, only linear height was significantly associated: adjusted HRs per 10‐cm increase were 0.85 (0.75–0.97) (p = 0.02) and 0.73 (0.57–0.92) (p = 0.009), respectively. For pelvic and rib fractures, the best models were for nonlinear BMI or weight (p = 0.05 and 0.03, respectively), with inverse associations at low BMI/body weight and positive associations at high values. These data demonstrate that the relationships between fracture and weight, BMI, and height are site‐specific. The different associations may be mediated, at least in part, by effects on bone mineral density, bone structure and geometry, and patterns of falling.

Intravenous Neridronate in Adults With Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a heritable disease of connective tissue, characterized by increased bone fragility. Bisphosphonates currently seems to be the most promising therapy, at least in children. We tested IV neridronate, an amino‐bisphosphonate structurally similar to alendronate and pamidronate in adults with OI. Twenty‐three men and 23 premenopausal women with OI were randomized to either iv neridronate (100 mg infused intravenously for 30 minutes every 3 months) or no treatment with a ratio of 2 to 1. Control patients were given the same bisphosphonate therapy at the end of the first year. Clinical evaluation included bone densitometry measurements using dual energy X‐ray absorptiometry (DXA), fasting serum and urinary biochemistry every 6 months, and radiographs of the spine taken at baseline and after 12 and 24 months of follow‐up. Spine and hip bone mineral density rose by 3.0 ± 4.6% (SD) and by 4.3 ± 3.9%, respectively, within the first 12 months of treatment, whereas small insignificant changes were observed in the control group. During the second year of follow‐up, additional 3.91% and 1.49% increases were observed at the spine and hip, respectively. Markers of skeletal turnover significantly fell during neridronate treatment. Fracture incidence during neridronate treatment was significantly lower than before therapy and compared with controls. Neridronate iv infusions, administered quarterly, significantly increase bone mineral density and lowered the risk of clinical fracture in adults with OI. Bisphosphonate therapy seems to provide clinical benefits, not only to children with OI, but also to adult patients.

Involvement of WNT/β-catenin Signaling in the Treatment of Osteoporosis

Osteoblast differentiation is predominantly regulated by the WNT/β-catenin signaling (canonical WNT pathway), which, together with bone morphogenetic proteins, acts as the master regulator of osteogenesis. The recent characterization of the canonical WNT pathway in the regulation of bone modeling and remodeling provided important insights for our understanding of the pathophysiology of a number of conditions and of the mechanism of action of hormones or drugs with important effect on bone metabolism. This review is mainly focused on the growing therapeutic implications of these new findings. WNT/β-catenin signaling plays a key role in bone tissue by determining the differentiation of stem cells into mature osteoblasts rather than into chondrocytes and adipocytes. Its regulation is predominantly driven by the production of two WNT signaling antagonists: sclerostin (SOST) and Dickkopf-related protein 1 (DKK1). The most proximate regulator of SOST expression by osteocytes and its serum levels is bone mechanical load. SOST expression is increased with advancing age, by glucocorticoid treatment and during treatment with antiresorptive agents such as bisphosphonates and denosumab, while it is decreased by parathyroid hormone excess or administration of estrogens. Correlation between DKK1 serum levels and bone formation in various pathological conditions or during osteoporosis treatment has been reported. Inhibitors of the negative regulators of WNT/β-catenin signaling (“inhibiting the endogenous inhibitors”) are potential candidates for the prevention and treatment of bone loss. Inactivating monoclonal antibodies against SOST appears to be the most attractive strategy because SOST is the only component of the WNT pathway expressed almost exclusively by osteocytes.