Vertebral fractures assessed with dual-energy X-ray absorptiometry in patients with Addison's disease on glucocorticoid and mineralocorticoid replacement therapy.

PURPOSE: to assess bone damage and metabolic abnormalities in patients with Addison's disease given replacement doses of glucocorticoids and mineralocorticoids. METHODS: A total of 87 patients and 81 age-matched and sex-matched healthy controls were studied. The following parameters were measured: urinary cortisol, serum calcium, phosphorus, creatinine, 24-h urinary calcium excretion, bone alkaline phosphatase, parathyroid hormone, serum CrossLaps, 25 hydroxyvitamin D, and 1,25 dihydroxyvitamin D. Clear vertebral images were obtained with dual-energy X-ray absorptiometry in 61 Addison's disease patients and 47 controls and assessed using Genant's classification. RESULTS: Nineteen Addison's disease patients (31.1%) had at least one morphometric vertebral fracture, as opposed to six controls (12.8%, odds ratio 3.09, 95% confidence interval 1.12-8.52). There were no significant differences in bone mineral density parameters at any site between patients and controls. In Addison's disease patients, there was a positive correlation between urinary cortisol and urinary calcium excretion. Patients with fractures had a longer history of disease than those without fractures. Patients taking fludrocortisone had a higher bone mineral density than untreated patients at all sites except the lumbar spine. CONCLUSIONS: Addison's disease patients have more fragile bones irrespective of any decrease in bone mineral density. Supra-physiological doses of glucocorticoids and longer-standing disease (with a consequently higher glucocorticoid intake) might be the main causes behind patients' increased bone fragility. Associated mineralocorticoid treatment seems to have a protective effect on bone mineral density.

Body Composition is Different After Surgical or Pharmacological Remission of Cushing's Syndrome: A Prospective DXA Study.

Patients with active Cushing's syndrome (CS) exhibit an increase of the visceral adipose tissue, increasing the risk of cardiovascular events. Until now, it is not yet clear whether remission of CS leads to a normalization of body composition, or if different strategies to control hypercortisolism could result in a different clinical outcome concerning adipose tissue distribution. Therefore, we analyzed body composition changes using dual-energy X-ray absorptiometry (DXA) in patients with CS in a prospective and controlled study. We considered 23 patients with CS, whose remission was achieved after surgery in 14 or gained with pharmacological treatment in 9 subjects. Clinical and DXA data (lean and fat mass in total body, trunk, and R1 box) were collected during active hypercortisolism and after sustained remission, defined as the normalization of both late night salivary and 24-h urinary cortisol levels, at least for 6 consecutive months. Healthy subjects, matched with CS for gender, age, and BMI, were considered as controls (n=25). After remission of hypercortisolism, body compositions of patients were similar to matched controls; fat mass in total body (-7.53%), trunk (-3.24%), and R1- box (-12.82%, all p<0.01) were decreased from baseline levels. Dividing patients by type of treatment, fat mass reduction was higher in those that achieved surgical remission of CS (total body -17.26%, trunk -22.73%, and R1 box -21.21%, all p<0.05). Surgical remission of hypercortisolism is characterized by improvement of body composition, particularly fat reduction, easily detectable with DXA during routine clinical practice.

Long-term glucocorticoid effect on bone mineral density in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

INTRODUCTION: Patients with 21-hydroxylase deficiency (21OHD) assume a lifelong glucocorticoid (GC) therapy. Excessive GC treatment increases the risk of osteoporosis and bone fractures, even though the role of substitutive therapy is not fully established: we analyzed the effect of GC dose on bone metabolism and bone mineral density (BMD) over time in patients with 21OHD. METHODS: We studied bone metabolism markers and BMD in 38 adult patients with 21OHD (19-47 years, 24 females and 14 males) and 38 matched healthy control. In 15 patients, BMD data were available at both baseline and after a long-term follow-up. RESULTS: BMD was lower in patients than in controls at lumbar spine (0.961±0.1g/cm(2) vs 1.02±0.113g/cm(2), P=0.014) and femur neck (0.736±0.128g/cm(2) vs 0.828±0.103g/cm(2), P=0.02); otherwise, after height correction, only femoral neck BMD was lower in patients (0.458±0.081g/cm(2) vs 0.498±0.063g/cm(2), P=0.028). In those 21OHD subjects with at least 10 years follow-up, we observed an increase in lumbar BMD (P=0.0429) and a decrease in femur neck BMD values (P=0.004). Cumulative GC dose was not related to bone metabolism or BMD. No patient experienced clinical fragility fractures. CONCLUSIONS: BMD values are decreased in patients with 21OHD, which are in part explained by decreased height, but not by the dose of glucocorticoids. Nevertheless, bone status should be carefully monitored in patients with 21OHD.

Genetic predictors of skeletal outcomes in healthy fertile women: the Bonturno study.

Skeletal traits as height (Ht) or bone mineral density (BMD) are strongly inherited. Low-density lipoprotein receptor-related protein 5 (LRP5) and farnesyl diphosphonate synthase (FDPS) are candidate genes for bone phenotypes. From Bonturno study, we genotyped 570 healthy Caucasian women aged 20 to 50 years (yrs) for LRP5 rs4988321 (A/G) and rs3736228 (C/T) and FDPS rs2297480 (A/C) single nucleotide polymorphisms. Serum C-telopeptide of type I collagen (CTX), osteocalcin (OC), and N-terminal propeptide of type I procollagen (P1NP) were measured in BMD-evaluated subjects at lumbar spine (LS), total hip (TH) and femoral neck (FN) sites. LRP5 rs4988321 locus correlated with FN-BMD (P = 0.0230), while LRP5 rs3736228 genotypes differed in LS-BMD (P = 0.0428). When clustered by age, lower FN-BMD was detected in LRP5 GG (P = 0.030) subjects of 41 to 50 years but not in younger. Both LRP5 GG and CC genotypes showed higher age-adjusted values of OC, CTX and P1NP. Increased CTX values were in LRP5 GGCC subjects than in those having at least one LRP5 A plus T alleles (P = 0.0190). LRP5 CC, GG or GGCC subjects with at least one FDPS C allele showed higher levels of CTX and OC in 31 to 40 yrs or older subjects. In conclusion, LRP5 and FDPS loci age-specifically affect skeletal traits in healthy fertile women.

Diagnosis of alterations of serum calcium metabolism.

Calcium is essential to homeostasis and functioning of multiple organ systems. Its circulating concentration is maintained within a very tight physiologic range: 2.25 and 2.50 mmol/L. Under physiological conditions, the ionized calcium concentration is regulated by the parathyroid hormone (PTH), and 1,25(OH)(2) vitamin D through interactions on target organs such as kidney, bone and intestine. In mild, moderate, and severe hypercalcemia, laboratory findings are essential in assessing and monitoring disease course and therapy. The main tools are specific standard biochemical tests able to assess calcium balance and renal function, and some specific biochemical tests, such as PTH, 25(OH) vitamin D, and genetic sequencing, used to clarify the cause of hypercalcemia and, subsequently, to determine appropriate therapy. Once hypercalcemia is confirmed by ionized calcium measurement, the intact PTH assay plays a crucial role to differentiate PTH-mediated from non-PTH-mediated hypercalcemia. Mild hypercalcemia is also present in up to 10-20% of patients treated with lithium for bipolar disorders, in 7-8% of those treated with thiazide diuretics, and in patients with prolonged immobilization, while very high (>3.5 mmol/L) serum calcium levels, together with low PTH, and a rapid increase of hypercalcemia, usually suggest a malignancy-associated hypercalcemic syndrome. The measurement of PTH-related protein, a tumor product that mimics certain action of PTH, is useful only in selected cases. The role of biochemical markers of bone turnover for predicting metastatic bone disease, and monitoring bone metabolic changes, and their usefulness as a predictive mean of the likelihood of bone loss or fractures risk is still unclear.

Treatment of acute hypercalcemia.

Acute hypercalcemia is a life-threatening rather rare condition. This condition may represent an acute decompensation of a pre-existing hypercalcemia, or may be acute at the first instance of the electrolyte disturbance. Hypercalcemic patients can present with a broad spectrum of symptoms, but most of them are mild and non-specific. Hypercalcemia affects a group of organs, which are considered together as a syndrome. The supportive care and ABC assessment are the first step to preserve vital functions. Severity index criteria should be considered at admission: severe dehydratation, mental status alteration, renal impairment, cardiac arrhythmias, ionized calcium level, nausea or vomiting, low social level. The neurological status and the main parameters (arterial blood pressure, cardiac pulses, oxygen saturation, temperature) must be monitored in all patients. Five keystones in the treatment of the hypercalcemic crisis should be considered: (1) Restore normovolemia to prevent renal impairment, (2) Restore renal function and enhance renal excretion of calcium, (3) Dialysis, (4) Inhibit osteoclastic bone resorption, and (5) Reduce intestinal calcium absorption. Currently, bisphosphonates are the drugs of choice in most of the patients after adequate hydration, while non-bisphosphonates drugs, such as calcitonin, gallium nitrate and mithramycin, are now rarely used. It is pivotal to recognize and treat the disease, according to evidence-based guidelines. At the same time, a short diagnostic program should be started to focus to the appropriate treatment of the underlying disease.

Treatment of chronic hypercalcemia.

Hypercalcemia is a relatively frequent alteration, mostly associated to primary hyperparathyroidism (PHPT) and malignancy-associated hypercalcemia (MAH). Treatment first includes rehydration and loop diuretics, as general measures. Bisphosphonates are considered the drugs of choice due to their long-term management. Calcitonin is preferable in the short-term control of severe hypercalcemia. The antireabsorptive action of bisphosphonates has been considered the most effective in the disorders characterized by an excessive bone resorption. Zoledronate is superior to both clodronate or pamidronate in the treatment of MAH. Calcimimetic agents has been recently introduced to control hypercalcemia in selected cases of PHPT. They are used when surgery is not possible or patients do not meet surgical criteria. Malignancy- associate hypercalcemia is broadly divided into two categories: humoral MAH and osteolytic MAH. The first concerns the paraneoplastic release of humoral factors, mainly parathyroid hormone-related peptide (PTHrP). Recently a humanized monoclonal antibody against human PTHrP has been generated and is still under evaluation. The receptor activator of nuclear factor-κ ligand (RANKL) has a critical role in the etiology of malignancy skeletal complications. The fully humanized anti-RANKL antibody (denosumab) would seem to be even more effective than bisphosphonates to suppress bone resorption, as shown in preliminary results .

Arterial blood pressure, serum calcium and PTH in elderly men with parathyroid tumors and primary hyperparathyroidism.

In patients with parathyroid tumors and primary hyperparathyroidism (PHPT), the relationship between arterial blood pressure (BP) and both serum calcium and parathyroid hormone (PTH) is still unclear. The aim of this study was to investigate whether a correlation exists between BP and the main biochemical parameters in men with confirmed sporadic PHPT due to a solitary parathyroid adenoma. A series of 38 elderly (>64 years) men (median age 69 years, range 65-78 years) were enrolled in the study. Twenty-nine (76.3%) were asymptomatic, while 9 (23.7%) had renal diseases (i.e. renal stones, impaired renal function). The main preoperative biochemical parameters were the following: serum calcium=2.77±0.25 mmol/l, PTH=166.5±157.0 ng/l, alkaline phosphatase (ALP)=107.6±37.0 U/l, and creatinine=82.5±8.1 µmol/l. In each patient, the BP was recorded three times at 2-3 min intervals using an automatic device, and the mean values were recorded. All patients successfully underwent parathyroidectomy. As expected, there was a significant relationship between age and both systolic and diastolic BP (ß=0.39, p=0.018; ß=0.41, p=0.014, respectively). There was also a correlation between systolic and diastolic BP (ß=0.39, p=0.01) and between serum calcium and PTH (ß=0.51, p=0.008). A weak relationship (ß=0.28, p=0.04) between serum calcium and creatinine was also found. However, no significant relationship between systolic or diastolic BP and serum calcium (ß=0.012, p=0.94; ß=0.065, p=0.71) or PTH (ß=0.08, p=0.65; ß=0.17, p=0.32), respectively, was observed. In conclusion, our study confirms that in men with parathyroid tumors and PHPT, the BP values are independent of both serum calcium and PTH levels.

Persistent increase of osteoprotegerin levels after cortisol normalization in patients with Cushing's syndrome.

OBJECTIVE: Osteoprotegerin (OPG) has been identified as a decoy receptor that inhibits osteoclast differentiation and, more recently, as a paracrine regulator of vascular calcification. OPG is suppressed by glucocorticoids (GC); however, results from experimental and clinical studies are not univocal. The aim of this study was to evaluate OPG and bone metabolism in patients with Cushing's syndrome (CS) before and after cure. DESIGN AND METHODS: Twenty-six patients with CS (all women, mean age: 39.1+/-11.9 years) and 24 age- and gonadal status-matched healthy women were studied for bone mineral density, bone metabolism, OPG, and receptor activator of nuclear factor-kB ligand at baseline. Twelve patients were also studied 6-18 months after surgery, with persistent normalization of cortisol levels. RESULTS: OPG was significantly higher and osteocalcin (OC) was significantly lower in CS patients than in controls (OPG: 4.17+/-1.23 vs 2.95+/-0.79 pmol/l, P=0.00001; OC: 15.0+/-6.1 vs 18.8+/-6.8 ng/ml, P=0.04 in CS and controls respectively). After cure, we found no difference in OPG levels, despite a significant increase in OC levels (from 16.4+/-11 to 37.2+/-15 ng/ml, P=0.03). CONCLUSION: Patients with CS showed increased OPG serum levels that remained unchanged after recovery, despite a restoration of bone formation. We speculate that high levels of OPG could reflect the persistent damage of the GCs on cardiovascular system.

Changes of bone formation markers osteocalcin and bone-specific alkaline phosphatase in postmenopausal women with osteoporosis.

The relationship between bone formation markers osteocalcin (OC) and bone-specific alkaline phosphatase (bALP) and age in postmenopausal women was investigated. Forty-eight osteoporotic women (median age 62, range 49-76 years) were enrolled in the study. There were 17 (35%) patients aged 49-59 years (Group A), and 31 (65%) patients aged over 59 years (Group B). Parathyroid hormone, calcium, and creatinine serum levels did not differ significantly between groups. Compared with Group A, patients in Group B had higher levels of both OC (28.5 +/- 17.8 versus 46.2 +/- 19.3 ng/mL; P= 0.003) and bALP (57.3 +/- 12.4 versus 66.4 +/- 8.7 U/L; P= 0.005). A significant relationship between age and both OC (R= 0.49, P= 0.002) and bALP (R= 0.41, P= 0.009) was found only in Group B, but there was no relationship with bone mineral density. In conclusion, in postmenopausal women the increase of bone formation markers later in life may be an expression of increased bone turnover, which is partially the cause of osteoporosis.

Bone mineral density, osteocalcin, and bone-specific alkaline phosphatase in patients with insulin-dependent diabetes mellitus.

The aims of this study were to evaluate the prevalence of osteopenia and the relationships between osteocalcin (OC), bone alkaline phosphatase (bALP), and bone mineral density (BMD) in patients with insulin-dependent diabetes mellitus (IDDM). A group of 18 patients (median age 47, range 36-51) with uncomplicated IDDM (Group A) were matched by sex, age, and body mass index with 21 healthy control volunteers (Group B). All subjects underwent osteodensitometry with measurement of BMD at the lumbar spine and femoral neck. Osteopenia was present in 11 (61.1%) and 2 (9.5%) of Group A and B patients (P= 0.01), respectively. Both OC (28.4 +/- 16.4 versus 41.2 +/- 14.6 ng/mL; P= 0.005) and bALP (51.3 +/- 11.8 versus 61.7 +/- 10.6 U/L; P= 0.006) serum levels were significantly lower in patients with IDDM. BMD did not correlate with either OC or bALP. In conclusion, osteopenia is common among patients with IDDM, but the relationship between bone formation markers and BMD is still unclear.

Age-specific effects of estrogen receptors' polymorphisms on the bone traits in healthy fertile women: the BONTURNO study.

BACKGROUND: Skeletal characteristics such as height (Ht), bone mineral density (BMD) or bone turnover markers are strongly inherited. Common variants in the genes encoding for estrogen receptor alpha (ESR1) and beta (ESR2) are proposed as candidates for influencing bone phenotypes at the population level. METHODS: We studied 641 healthy premenopausal women aged 20-50 years (yrs) participating into the BONTURNO study. Exclusion criteria were irregular cyclic menses, low trauma fracture, metabolic bone or chronic diseases. Serum C-telopeptide of type I collagen (CTX), osteocalcin (OC), and N-terminal propeptide of type I procollagen (P1NP) were measured in all enrolled subjects, who underwent to lumbar spine (LS), total hip (TH) and femoral neck (FN) BMD evaluation by DXA. Five hundred seventy Caucasian women were genotyped for ESR1 rs2234693 and rs9340799 and ESR2 rs4986938 polymorphisms. RESULTS: Although no genotype differences were found in body parameters, subjects with combined ESR1 CCGG plus ESR2 AA-AG genotype were taller than those with opposite genotype (P = 0.044). Moreover, ESR1 rs2234693 genotypes correlated with family history of osteoporosis (FHO) and hip fracture (FHF) (P < 0.01), while ESR2 AA-AC genotypes were strongly associated with FHF (OR 2.387, 95% CI 1.432-3.977; P < 0.001).When clustered by age, 20-30 yrs old subjects, having at least one ESR1 rs2234693 C allele presented lower LS- (P = 0.008) and TH-BMD (P = 0.047) than TT genotypes. In 41-50 yrs age, lower FN-BMD was associated with ESR2 AA (P = 0.0180) subjects than in those with the opposite genotype. ESR1 rs2234693 and rs9340799 and ESR2 rs4986938 polymorphisms did not correlate with age-adjusted values of OC, CTX and P1NP. CONCLUSION: These findings support the presence of age-specific effects of ESR1 and ESR2 polymorphisms on various skeletal traits in healthy fertile women.

Physical activity and bone turnover markers: a cross-sectional and a longitudinal study.

Strenuous physical activity in young individuals has an important effect on both bone mass and bone turnover but the effect of moderate physical activity in adults remains uncertain. In a large cohort (N = 530) of healthy premenopausal women, bone formation markers (osteocalcin and N-terminal propeptide of type 1 procollagen [P1NP]), but not serum C-telopeptide of type 1 collagen (sCTX), were found to be significantly associated with the level of physical activity, and this association remained significant after adjusting the data (ANCOVA) by age and body mass index. Mean spine and hip bone mineral density (BMD) values were positively associated with physical activity but this was statistically significant (P = 0.050) only for adjusted values of spine BMD. Twenty-four healthy sedentary premenopausal women, subscribing to participate in a community exercise program lasting a month, and 18 age-matched controls were included in the longitudinal study. Serum osteocalcin and P1NP, but not sCTX, rose significantly, by ca. 25%, only in the active group after a month of exercise. The changes in the two bone formation markers remained statistically significant for values adjusted for body weight, which fell significantly in the exercise group. In conclusion, both the cross-sectional and the longitudinal parts of our study demonstrate that even minor changes in physical activity are associated with a clear effect on bone formation markers.

Quantitative ultrasound technology in evaluating bone status and osteoporosis in patients with Cushing's syndrome.

Osteoporosis is a major feature of Cushing's syndrome (CS), and fragility fractures may be the first sign of the disease. The aim of this study was to evaluate the ability of quantitative ultrasound technology (QUS) in diagnosing osteoporosis in patients with CS. Sixty-three consecutive patients (mean age 38.6 +/- 13.0 years), 13 (20.6%) men and 50 (79.4%) women, with confirmed CS underwent both dual-energy X-ray densitometry (DXA) and QUS. Two groups of patients were selected: group A, 23 patients, T-score -2 SD or less (bone mineral density [BMD] femoral neck < or = 695 g/cm(2)), and group B, 40 patients, T-score above -2 SD. Age (42 +/- 12 vs. 37 +/- 13 years) and 24-h free urinary cortisol (499 +/- 345 vs. 469 +/- 319 microg/day) did not differ significantly (P = NS) between groups, while the body mass index did (24.3 +/- 4.1 vs. 28.1 +/- 4.6, P = 0.002). Unlike DXA, QUS values did not differ significantly (P = NS) between groups. Moreover, in the overall population, as well as in a single group, there was no correlation (R < 0.5, P = NS) between QUS and DXA parameters. In conclusion, in our study QUS was not able to differentiate osteoporotic patients from those with normal BMD measured by DXA, and thus QUS technology should not be used to discriminate between osteopenic and nonosteopenic patients with CS.

Bone mineral density improvement after successful parathyroidectomy in pre- and postmenopausal women with primary hyperparathyroidism: a prospective study.

The aim of this study was to evaluate the short-term (1 year) changes of the lumbar spine (L2-L4) bone mineral density (LS-BMD) after parathyroidectomy (PTx) in pre- and postmenopausal women with primary hyperparathyroidism (PHPT). A series of 48 women (median age 56 years, range 23-82 years) with confirmed PHPT were prospectively enrolled in the study. Patients who received both oral contraceptives less than 2 years before the diagnosis and estrogen replacement therapy have previously been excluded. All patients underwent LS-BMD by dual energy x-ray absorptiometry before surgery. Patients were divided into two groups: group A (n = 12) premenopausal, and group B (n = 36) postmenopausal patients. The LS-BMD was repeated 12 months after successful PTx. Basal LS-BMD (0.852 +/- 0.061 vs. 0.748 +/- 0.142 g/cm(2)), serum calcium (2.95 +/- 0.23 vs. 2.94 +/- 0.26 mmol/L), creatinine (69.2 +/- 17.5 vs. 82.0 +/- 24.2 micromol/L), alkaline phosphatase (107.4 +/- 43.6 vs. 151.3 +/- 95.7 U/L), osteocalcin (28.6 +/- 9.3 vs. 28.2 +/- 8.3 microg/L), and PTH (192.7 +/- 133.2 vs. 175.2 +/- 132.1 ng/L) levels did not differ significantly (P = NS) between groups. The 1-year LS-BMD was 0.921 +/- 0.048 and 0.825 +/- 0.151 g/cm(2) in group A and B, respectively. In group B patients, the 1-year LS-BMD value did not improve significantly (P = NS), while in group A patients the difference between basal and postsurgical LS-BMD was significant (P < 0.01). In conclusion, PTx should be considered for all patients with PHPT and loss of bone density, but in premenopausal patients a greatest improvement of BMD may be found, suggesting the need of endogenous estrogens in complete lumbar bone recovery after surgery.

Lumbar spine bone mineral density changes in patients with primary hyperparathyroidism according to age and gender.

Primary hyperparathyroidism (PHPT) results from excessive secretion of parathyroid hormone (PTH), and catabolic and anabolic effects of PTH on bone may lead to overall deleterious effects on skeleton. The aim of this study was to analyze the changes in lumbar spine bone mineral density (BMD) in patients with PHPT who underwent parathyroidectomy (PTx), and to correlate the main demographics and biochemical parameters with pre- and postoperative BMD values. Two groups of age-matched patients (group A = 14 postmenopausal women; group B = 13 men, overall median age 53 years, range 26-56 years) with confirmed PHPT were enrolled in the study. All patients underwent lumbar (L2-L4 region) spine osteodensitometry using a dual-energy X-ray absorptiometry (DXA) prior to surgery. A significant correlation between alkaline phosphatase (ALP) and PTH (R = 0.73, P = 0.003) was found in group A patients. In group B correlations were found between calcemia and ALP (R = 0.71, P = 0.007), and between osteocalcin and both PTH (R = 0.65, P = 0.01) and ALP (R = 0.59, P = 0.03). No correlation (P = NS) was found between BMD, both basal and postoperative, and age or biochemical parameters. The 1-year BMD were 0.937 +/- 0.115 and 0.940 +/- 0.201 g/cm(2) (P = NS) in group A and B, respectively. A significant (P = 0.03) difference between basal and 1-year BMD was found only in group A, while in group B the difference was not significant. In conclusion, in patients with PHPT bone turnover is increased and consequently the BMD is reduced, but unfortunately PTx does not allow for complete bone restoring. However, in premenopausal women the BMD values of the lumbar spine significantly improve after PTx, suggesting a higher bone sensitivity to serum PTH normalization due to a synergic action with estrogens.

Quantitative bone ultrasound at phalanges and calcaneus in osteoporotic postmenopausal women: influence of age and measurement site.

Phalangeal and calcaneal quantitative ultrasound (QUS) measurements were tested in a postmenopausal osteoporotic population of a wide age range to assess their ability to identify subjects with vertebral fractures in a population of postmenopausal women with osteoporosis. A group of 127 osteoporotic women aged from 50 to 85 y, who had been postmenopausal for at least 5 y, were enrolled. All subjects underwent phalangeal and calcaneal QUS measurements, femoral neck and lumbar spine dual energy X-ray absorptiometry (DXA) measurements and lateral thoracic and lumbar spine radiography. Osteoporosis was defined on the basis of femoral neck or lumbar spine bone mineral density (BMD) T-score lower than -2.5 SD or of the presence of one or more vertebral atraumatic fractures, independently of BMD values. Fifty-two women had one or more vertebral fractures, while the remaining 75 had no evidence of previous fracture. Both QUS techniques were able to discriminate between fractured and nonfractured subjects in the whole group (p < 0.05). When patients aged <70 y (n = 43) and patients aged > or = 70 y (n = 84) were considered separately, phalangeal QUS and lumbar spine BMD were able to discriminate vertebral fractures in the younger group (p < 0.05), whereas calcaneal QUS was able to discriminate vertebral fractures in the older one (p < 0.05). The results of this study raise an issue of the optimal use of different QUS techniques and different skeletal sites in the management of osteoporosis in early or late postmenopausal life.

Fracture incidence and characterization in patients on osteoporosis treatment: the ICARO study.

UNLABELLED: None of the available osteoporosis therapies have been shown to completely abolish the risk of fractures. In clinical practice, the outcome may be even poorer. In 880 patients prescribed with antiresorptives (alendronate, risedronate, and raloxifene) for >1 year, a fragility fracture was recorded in 8.9%/year of them. This incidence is considerably higher than that observed in randomized clinical trials, and it was significantly related to poor compliance and lack of supplementation with calcium and vitamin D. INTRODUCTION: Osteoporotic fracture is one of the most important public health concerns among the elderly. Currently available therapies have been shown to significantly decrease the risk of fracture, although none of them completely abolishes this risk. In clinical practice, poor treatment response may also result from a number of other factors. MATERIALS AND METHODS: The Incidence and ChAracterization of inadequate clinical Responders in Osteoporosis (ICARO) is a multicenter, observational study carried out in Italy. It aimed to analyze, in postmenopausal women with established osteoporosis, the risk factors for an "inadequate clinical response" to drug therapy, defined as the occurrence of new vertebral or nonvertebral fragility fractures in patients prescribed, for at least 1 year, alendronate, risedronate, or raloxifene, with a compliance >50%. RESULTS: In 880 patients treated with antiresorptive agents for a median of 2.0 years (95% CI: 1.0-4.5) years, the "inadequate clinical responder (ICR)" subjects over the observation period were 220 (25%), with an annual incidence of 8.9%. ICRs, compared with "adequate clinical responders (ACRs)," had more pretreatment fractures and were treated longer (2.8 versus 1.8 years; p < 0.001). After multiple adjustment for these confounding factors, significant determinants of inadequate clinical response were a poorer treatment compliance and a less frequent co-administration of calcium and vitamin D supplements. CONCLUSIONS: The incidence of fractures during treatment with antiresorptive agents in a clinical setting is considerably higher than that observed in randomized clinical trials. Inadequate compliance to treatment and lack of supplementation of calcium and vitamin D are major determinants of this poor response.

Vertebral fracture risk reduction with strontium ranelate in women with postmenopausal osteoporosis is independent of baseline risk factors.

UNLABELLED: Strontium ranelate (2 g/day) was studied in 5082 postmenopausal women. A reduction in incident vertebral fracture risk by 40% was shown after 3 years. This effect was independent of age, initial BMD, and prevalent vertebral fractures. INTRODUCTION: Strontium ranelate is an orally active treatment able to decrease the risk of vertebral and hip fractures in osteoporotic postmenopausal women. The aim of this study was to assess the efficacy of strontium ranelate according to the main determinants of vertebral fracture risk: age, baseline BMD, prevalent fractures, family history of osteoporosis, baseline BMI, and addiction to smoking. MATERIALS AND METHODS: We pooled data of two large multinational randomized double-blind studies with a population of 5082 (2536 receiving strontium ranelate 2 g/day and 2546 receiving a placebo), 74 years of age on average, and a 3-year follow-up. An intention-to-treat principle was used, as well as a Cox model for comparison and relative risks. RESULTS: The treatment decreased the risk of both vertebral (relative risk [RR] = 0.60 [0.53-0.69] p < 0.001) and nonvertebral (RR = 0.85 [0.74-0.99] p = 0.03) fractures. The decrease in risk of vertebral fractures was 37% (p = 0.003) in women <70 years, 42% (p < 0.001) for those 70-80 years of age, and 32% (p = 0.013) for those > or = 80 years. The RR of vertebral fracture was 0.28 (0.07-0.99) in osteopenic and 0.61 (0.53-0.70) in osteoporotic women, and baseline BMD was not a determinant of efficacy. The incidence of vertebral fractures in the placebo group increased with the number of prevalent vertebral fractures, but this was not a determinant of the effect of strontium ranelate. In 2605 patients, the risk of experiencing a first vertebral fracture was reduced by 48% (p < 0.001). The risk of experiencing a second vertebral fracture was reduced by 45% (p < 0.001; 1100 patients). Moreover, the risk of experiencing more than two vertebral fractures was reduced by 33% (p < 0.001; 1365 patients). Family history of osteoporosis, baseline BMI, and addiction to smoking were not determinants of efficacy. CONCLUSIONS: This study shows that a 3-year treatment with strontium ranelate leads to antivertebral fracture efficacy in postmenopausal women independently of baseline osteoporotic risk factors.

Effect of licorice on PTH levels in healthy women.

UNLABELLED: Licorice has been considered a medicinal plant for thousands of years. Its most common side effect is hypokalemic hypertension, which is secondary to a block of 11beta-hydroxysteroid dehydrogenase type 2 at the level of the kidney, leading to an enhanced mineralocorticoid effect of cortisol. This effect is due to glycyrrhetinic acid, which is the main constituent of the root, but other components are also present, including isoflavans, which have estrogen-like activity, and are thus involved in the modulation of bone metabolism. We investigated nine healthy women 22-26 years old, in the luteal phase of the cycle. They were given 3.5 g of a commercial preparation of licorice (containing 7.6%, w/w of glycyrrhizic acid) daily for 2 months. Plasma renin activity (PRA), aldosterone, cortisol, serum parathyroid hormone (PTH), 1,25-dihydroxy Vitamin D (1,25OHD), 25-hydroxycholecalciferol (25OHD), estradiol, FHS, LH, alkaline phosphatase (ALP), calcium, phosphate and creatinine, urinary calcium and phosphate and mineralometry were measured. PTH, 25OHD and urinary calcium increased significantly from baseline values after 2 months of therapy, while 1,25OHD and ALP did not change during treatment. All these parameters returned to pretreatment levels 1 month after discontinuation of licorice. PRA and aldosterone were depressed during therapy, while blood pressure and plasma cortisol remained unchanged. CONCLUSIONS: licorice can increase serum PTH and urinary calcium levels from baseline value in healthy women after only 2 months of treatment. The effect of licorice on calcium metabolism is probably influenced by several components of the root, which show aldosterone-like, estrogen-like and antiandrogen activity.