V. Braga

Bisphosphonate therapy of reflex sympathetic dystrophy syndrome

OBJECTIVE The reflex sympathetic dystrophy syndrome (RSDS) is a painful limb disorder, for which a consistently effective treatment has not yet been identified. The disease is associated with increased bone resorption and patchy osteoporosis, which might benefit from treatment with bisphosphonates, powerful inhibitors of bone resorption. METHODS Twenty patients with RSDS of foot and hand, were randomly assigned to blind administration of either alendronate intravenously (Istituto Gentili, Pisa, Italy) 7.5 mg dissolved in 250 ml saline solution or placebo saline infusions daily for three days. Two weeks later all patients had an identical treatment course with open labelled alendronate (7.5 mg/day for three days), independent from the results of the first blind treatment. RESULTS In the patients treated with blind alendronate the diminution in spontaneous pain, tenderness, and swelling (circumference of the affected limb) and the improvement in motion were significantly different from baseline (p<0.001), from those observed within the first two weeks in the control group (p<0.01), and from week 2 to week 4 (p<0.01). In the patients given blind placebo infusions no relevant symptomatic changes were observed after the first two weeks of follow up, but they responded to the open alendronate therapy given afterwards. In 12 patients with RSDS of the hand the ultradistal bone mineral content (BMC) of the affected arm was considerably lower than that of the controlateral arm (mean (SD)) (426(82) mg/cm versus 688(49)). Six weeks after the beginning of the trial BMC rose by 77(12) mg/cm (p<0.001) in the affected arm, but it did not change in the controlateral. CONCLUSIONS These results indicate that bisphosphonates should be considered for the treatment of RSDS, producing consistent and rapid remission of the disease.

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.

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.

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.

Chronic Intravenous Aminobisphosphonate Therapy Increases High‐Density Lipoprotein Cholesterol and Decreases Low‐Density Lipoprotein Cholesterol

Nowadays, bisphosphonates are considered the drugs of choice for the treatment of several bone disorders. Their exact mechanism of action is not clear but recently it has been reported that the aminobisphosphonates inhibit cholesterol biosynthesis and that this might be relevant for their actions on bone osteoclasts. The study includes 87 postmenopausal women with moderate to severe osteoporosis. The patients were randomly assigned to intravenous (iv) infusion of 50 mg of the aminobisphosphonate Neridronate dissolved in 100 ml of saline solution every 2 months for a year (44 patients). The remaining 43 served as controls. At the time of each infusion blood samples were obtained for the evaluation of total cholesterol, triglycerides, high‐density lipoprotein cholesterol (HDL‐C) and low‐density lipoprotein cholesterol (LDL‐C), apolipoprotein A‐I (Apo A‐I), apolipoprotein B (Apo B), and total and bone alkaline phosphatase (AP). Free deoxypyridinoline (f‐DPD) was measured in fasting urine specimens. In the control group no significant changes were observed throughout the study period for any of the biochemical variables. In the Neridronate‐treated patients both bone AP and f‐DPD excretion fell significantly by 15–20%. In these patients serum total cholesterol and serum triglycerides showed marginal decreases, which were occasionally significant. LDL‐C and Apo B fell by 5–6% and these changes were statistically significant at most time points. Apo A‐I and HDL‐C rose progressively with time. At the 12th month, HDL‐C rose 17–18% (p < 0.0001) above the baseline values. Similar findings were obtained in four postmenopausal women given high iv doses of Pamidronate or Alendronate. In conclusion aminobisphophonates, at least when given iv, induce remarkable and unexpected effects on lipid metabolism with a final profile that might be clinically relevant.

Drug-induced morphea: Report of a case induced by balicatib and review of the literature

Drug-induced scleroderma has been rarely reported, mostly with the features of diffuse scleroderma or acrosclerosis, and exceptionally with the characteristics of morphea. We report the case of an adult white woman, enrolled in a double-blind, placebo-controlled, multicentric trial evaluating the efficacy and safety of the cathepsin K inhibitor balicatib for osteoporosis. Typical morphea lesions developed on the patients trunk 9 months after the beginning of therapy. Lesions completely resolved after drug withdrawal and a single brief course of systemic steroids. No recurrence occurred in a 2-year follow-up. Fifteen cases of drug-induced morphea could be retrieved from the literature. Drug withdrawal determined complete remission in only a few patients. Different drug classes have been implicated. Some of these, including balicatib, alter directly connective tissue metabolism.

Effect of aging on trabecular and compact bone components of proximal and ultradistal radius

Bone densitometry has become a major tool for osteoporosis risk assessment. The traditional dual-energy X-ray absorptiometry (DXA) methods are able to evaluate the bone mineral content (BMC; mg/cm) and the areal density (BMD; mg/cm2), but only quantitative computed tomography (QCT) has the potential to measure the true volumetric bone density in the sense of mass per unit volume (mg/cm3). Peripheral QCT (pQCT) measurements were carried out at the non-dominant radius using a Stratec XCT 960 (Unitrem, Roma) in 241 postmenopausal and 29 premenopausal women. The sites of evaluation were both the ultradistal and the proximal radius. The technique used has a coefficient of variation of 2% and it allows separation of the bone section into trabecular and cortical bone on the basis of density threshold. Bone mass of radius, hip and spine was also evaluated by DXA procedures. The bone density data obtained by pQCT were significantly correlated with all DXA measurements. The correlation coefficients between their respective BMD values ranged from 0.48 to 0.75, but for the BMC values of the radius the correlation coefficients ranged from 0.82 to 0.93. The BMD values measured by DXA, but not by pQCT, were positively related with patient heights. All pQCT density measurements, including those obtained at the proximal radius and containing exclusively cortical bone, where negatively related with age and years since menopause. A partial volume effect, which is increasingly relevant the thinner are the bone cortices, might explain that. However, by applying increasing density thresholds, cortical bone density seems to decrease with age as a consequence of a gradual density diminution from the inner part of the bone cortex outwards. Trabecular bone density decreases with aging, but its overall mass does not change as a consequence of an age-related enlargement of trabecular area. Thus, the proportion of trabecular bone over total bone rises, and this might be relevant for our understanding of the age-related changes in bone turnover and rate of bone loss.

25-hydroxy vitamin D levels in healthy premenopausal women: association with bone turnover markers and bone mineral density.

BACKGROUND Vitamin D deficiency is very common in elderly people while there are very few reports on its incidence, determinants and metabolic consequences in young subjects. RESULTS In 608 young healthy premenopausal women participating in the BONTURNO study, levels of 25-hydroxyvitamin D [25(OH)D] below 20 ng/ml were found in almost a third of the women. Its levels were inversely (P<0.001) related with age and body mass index (BMI kg/m(2)) and directly with sunlight exposure during the summer time, and latitude: i.e. the higher the latitude over Italy, the higher the 25(OH)D level. In women on contraceptive pill the mean 25(OH)D level was significantly increased even when the data were adjusted for age, BMI and sun exposure. 25(OH)D levels, adjusted for age and BMI, were significantly and positively related with serum C-telopeptide of type 1 collagen, serum phosphate and spine bone mineral density (BMD) and negatively with serum PTH, serum magnesium, serum bone alkaline phosphatase (bone AP). CONCLUSION Vitamin D deficiency is rather common in young otherwise healthy Italian women and particularly among those living in the Southern part of the country. The most close determinants of vitamin D deficiency were BMI and sunlight exposure. Vitamin D insufficiency is associated with low spine BMD and increased bone AP even in young individuals.