S. Minisola

Comparative effects of teriparatide and risedronate in glucocorticoid-induced osteoporosis in men: 18-month results of the EuroGIOPs trial.

Data on treatment of glucocorticoid‐induced osteoporosis (GIO) in men are scarce. We performed a randomized, open‐label trial in men who have taken glucocorticoids (GC) for ≥3 months, and had an areal bone mineral density (aBMD) T‐score ≤ –1.5 standard deviations. Subjects received 20u2009μg/d teriparatide (nu2009=u200945) or 35u2009mg/week risedronate (nu2009=u200947) for 18 months. Primary objective was to compare lumbar spine (L1–L3) BMD measured by quantitative computed tomography (QCT). Secondary outcomes included BMD and microstructure measured by high‐resolution QCT (HRQCT) at the 12th thoracic vertebra, biomechanical effects for axial compression, anterior bending, and axial torsion evaluated by finite element (FE) analysis from HRQCT data, aBMD by dual X‐ray absorptiometry, biochemical markers, and safety. Computed tomography scans were performed at 0, 6, and 18 months. A mixed model repeated measures analysis was performed to compare changes from baseline between groups. Mean age was 56.3 years. Median GC dose and duration were 8.8u2009mg/d and 6.4 years, respectively; 39.1% of subjects had a prevalent fracture, and 32.6% received prior bisphosphonate treatment. At 18 months, trabecular BMD had significantly increased for both treatments, with significantly greater increases with teriparatide (16.3% versus 3.8%; pu2009=u20090.004). HRQCT trabecular and cortical variables significantly increased for both treatments with significantly larger improvements for teriparatide for integral and trabecular BMD and bone surface to volume ratio (BS/BV) as a microstructural measure. Vertebral strength increases at 18 months were significant in both groups (teriparatide: 26.0% to 34.0%; risedronate: 4.2% to 6.7%), with significantly higher increases in the teriparatide group for all loading modes (0.005u2009<u2009pu2009<u20090.015). Adverse events were similar between groups. None of the patients on teriparatide but five (10.6%) on risedronate developed new clinical fractures (pu2009=u20090.056). In conclusion, in this 18‐month trial in men with GIO, teriparatide showed larger improvements in spinal BMD, microstructure, and FE‐derived strength than risedronate.

Guidelines for the diagnosis, prevention and management of osteoporosis.

Osteoporosis poses a significant public health issue. National Societies have developed Guidelines for the diagnosis and treatment of this disorder with an effort of adapting specific tools for risk assessment on the peculiar characteristics of a given population. The Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS) has recently revised the previously published Guidelines on the diagnosis, riskassessment, prevention and management of primary and secondary osteoporosis. The guidelines were first drafted by a working group and then approved by the board of SIOMMMS. Subsequently they received also the endorsement of other major Scientific Societies that deal with bone metabolic disease. These recommendations are based on systematic reviews of the best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on leading experts experience and opinion, and on good clinical practice. The osteoporosis prevention should be based on the elimination of specific risk factors. The use of drugs registered for the treatment of osteoporosis are recommended when the benefits overcome the risk, and this is the case only when the risk of fracture is rather high as measured with variables susceptible to pharmacological effect. DeFRA (FRAX® derived fracture risk assessment) is recognized as a useful tool for easily estimate the long-term fracture risk. Several secondary forms of osteoporosis require a specific diagnostic and therapeutic management.

Early changes in biochemical markers of bone formation during teriparatide therapy correlate with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis

SummaryChanges of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide.IntroductionTo investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO.MethodsA total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20xa0μg/day, nu2009=u200945) and risedronate (35 mg/week, nu2009=u200947). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables.ResultsPINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA-derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group.ConclusionsPositive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients.

Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial

BACKGROUNDnNo clinical trials have compared osteoporosis drugs with incident fractures as the primary outcome. We compared the anti-fracture efficacy of teriparatide with risedronate in patients with severe osteoporosis.nnnMETHODSnIn this double-blind, double-dummy trial, we enrolled post-menopausal women with at least two moderate or one severe vertebral fracture and a bone mineral density T score of less than or equal to -1·50. Participants were randomly assigned to receive 20 μg of teriparatide once daily plus oral weekly placebo or 35 mg of oral risedronate once weekly plus daily injections of placebo for 24 months. The primary outcome was new radiographic vertebral fractures. Secondary, gated outcomes included new and worsened radiographic vertebral fractures, clinical fractures (a composite of non-vertebral and symptomatic vertebral), and non-vertebral fractures. This study is registered with ClinicalTrials.gov (NCT01709110) and EudraCT (2012-000123-41).nnnFINDINGSnWe enrolled 680 patients in each group. At 24 months, new vertebral fractures occurred in 28 (5·4%) of 680 patients in the teriparatide group and 64 (12·0%) of 680 patients in the risedronate group (risk ratio 0·44, 95% CI 0·29-0·68; p<0·0001). Clinical fractures occurred in 30 (4·8%) of 680 patients in the teriparatide group compared with 61 (9·8%) of 680 in the risedronate group (hazard ratio 0·48, 95% CI 0·32-0·74; p=0·0009). Non-vertebral fragility fractures occurred in 25 (4·0%) patients in the teriparatide group and 38 (6·1%) in the risedronate group (hazard ratio 0·66; 95% CI 0·39-1·10; p=0·10).nnnINTERPRETATIONnAmong post-menopausal women with severe osteoporosis, the risk of new vertebral and clinical fractures is significantly lower in patients receiving teriparatide than in those receiving risedronate.nnnFUNDINGnLilly.

The acute myocardial infarction in very elderly.

A total 325 patients were studied at admission for myocardial infarction, measuring plasma fibrinogen (FBG), creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) and automatized hemocromocytometric parameters in order to contribute to explain the excess mortality reported in very elderly patients. It was found that age positively correlated with fibrinogen and LDH values and inversely with CPK, hemoglobin concentration and lymphocyte count. The unpaired comparison of the variables studied in age subgroups showed no differences between patients aged 65 or less than 65 years and patients aged 66-75 years. In patients aged over 75 years FBG, neutrophile count and LDH were significantly higher in respect to 65 or less and 66-75 years age subgroups and hemoglobin concentration, red blood cell count, hematocrit and lymphocyte count were lower. In the very elderly patients the study shows a biochemical feature suggesting delayed hospitalization for myocardial infarction, that may contribute to their poorer prognosis.

CLINICAL-SIGNIFICANCE OF FREE PLASMA HYDROXYPROLINE MEASUREMENT IN METABOLIC BONE-DISEASE

Free hydroxyproline was measured in plasma of 67 normal subjects and in 70 patients with bone disease including primary hyperparathyroidism (n = 19), osteoporosis (n = 18), Pagets disease (n = 14), cancer involving bone (n = 8), chronic renal failure (n = 6), and osteomalacia (n = 6), and osteomalacia (n = 5). A good correlation was found between plasma and urinary values of the amino acid in normal subjects (r = 0.66; p less than 0.001). In patients with skeletal disorders a highly significant direct correlation was observed between free plasma hydroxyproline on the one hand and urinary hydroxyproline (r = 0.92; p less than 0.001) and serum alkaline phosphatase activity (r = 0.86; p less than 0.001) on the other, even though there were a few examples of dissociations among these parameters. Free plasma hydroxyproline decreased in the patients with Pagets disease following chronic administration of salmon calcitonin. Following successful parathyroidectomy, free plasma levels of hydroxyproline decreased in all the cases studied. Measurement of free plasma hydroxyproline thus appears to provide a specific index of bone metabolism that may be usefully employed as an alternative to the assay of other markers of bone turnover.

Effect of risedronate in osteoporotic HIV males, according to gonadal status: a pilot study

The aim of the study was to evaluate the effect of risedronate on bone mineral density (BMD) and bone turnover markers in HIV-infected osteoporotic males, according to their gonadal status. HIV patients were followed up for 24xa0months and divided into two groups: patients with osteoporosis or osteopenia with fractures (group A, nxa0=xa020) and those without (group B, nxa0=xa021). Group A and B were further divided according to the presence of reduced androgenizations. Both groups were treated with cholecalciferol 800 I.U. and calcium (Ca) 1,000xa0mg orally every day for the first 12xa0months. Risedronate 75xa0mg for two consecutive days a month orally was then added in group A, for another 12xa0months. Group B continued treatment with Ca and vitamin D. Every 6xa0months each patient underwent biochemical evaluation, and BMD measurement. A significant increase in lumbar BMD was observed in HIV males with adequate androgenization after 12xa0months of risedronate treatment in group A together with a reduction of bone turnover markers. BMD remained stable with a concomitant significant slight reduction of bone turnover markers in group B. Risedronate increased BMD and reduced bone turnover markers to a greater extent in patients with adequate androgenization compared to osteoporotic HIV males with symptomatic hypoandrogenization.

Six-year follow-up of a characteristic osteolytic lesion in a patient with tumor-induced osteomalacia

OBJECTIVEnTumor-induced osteomalacia is a rare paraneoplastic syndrome characterized by hypophosphatemia and inappropriately normal or low 1,25-dihydroxyvitamin D.nnnCLINICAL CASEnHere, we report a 6-year postoperative follow-up of a patient with oncogenic osteomalacia with a distinctive skeletal manifestation. The latter was characterized by an almost linear lytic lesion of a few millimeters with irregular borders, mainly involving the trabecular compartment but extending into cortical shell, located in the middle third of the right fibula. Six years after tumor resection, a sclerotic repair with a complete recovery was observed. Furthermore, we monitored a striking increase in bone mineral density throughout the observation period, reaching a peak of 73% over basal values at lumbar spine after 2 years; at total femur and radius, the peak was 47.5 and 4.6% respectively, after 4 years from tumor resection.nnnCONCLUSIONSnWe report for the first time that an osteolytic lesion may be part of the skeletal involvement in tumor-induced osteomalacia.

Massive Tumoral Calcinosis in a Patient on Long‐Term Hemodialysis

A 37-year-old man with end-stage renal disease caused by glomerulonephritis had been undergoing dialysis since 1987. In 1990, he started complaining of pain in both shoulders and in the right hip. A plain radiograph revealed soft tissue calcifications proximate to these three joints. In 1993, owing to unbearable pain with functional limitation, an X-ray was repeated that showed a dramatic lobular periarticular calcification (Fig. 1A, right hip). The patient had been compliant in taking aluminumcontaining phosphate binders and had been treated with oral calcitriol. He came to our attention in 1995 owing to pain, palpable calcifications on both shoulders, and stiffness in the same articulations and in the right hip. He had a slight elevation of calcium-phosphate product (Ca, 10.10 mg/dl;p 5 5.45 mg/dl) and normal values for both 25-hydroxyvitamin D [25(OH)D; 32 ng/ml, normal values (nv), 10 – 40 ng/ml] and 1,25(OH) 2D (25 pg/ml; nv5 16 –58 pg/ml), parathyroid hormone (41.5 pg/ml; nv, 10.6 –54 pg/ml), and isoenzyme of total alkaline phosphatase (16.3 U/liter; normal values (nv), 9.4 –26.2 U/liter). He refused any further radiographic approach except for the measurement of a whole body bone mineral density; this documented the effect of the calcification at the above-mentioned sites (Fig. 1B). The patient, lost at the follow-up, was again contacted at the beginning of 1998; his conditions had worsened so that he was almost unable to move his arms and walking was almost impossible. He agreed to perform a whole body calcium measurement again (Fig. 1C). This documented an increase of global bone mineral content despite a reduction in all the subregions unaffected by the extraskeletal calcification process; this increase was most likely caused by the growing calcinosis masses. The patient was advised to start treatment with sodium thiosulfate based on the few studies available in the literature (1,2) while continuing monitor ing phosphate values with conventional drugs, but unfortunately, he failed to follow this therapy. Even though the pathogenesis of massive periarticular calcifications in dialysis patients is unknown, it is possible that abnormalities of vitamin D metabolism might substantially contribute, as previously suggested by Quarles and coworkers. (3) In fact, our patient also had inappropriately normal values of 1,25(OH) 2D for the degree of renal func tion and hyperphosphatemia. Finally, this report underscores the difficult therapeutic challenge posed by these infrequent manifestations of chronic renal failure.

Vitamin D: not all is bad

Dr Reid recently published an ‘‘Opinion’’ in our journal [1] reconsidering some of the actions of vitamin D on the basis of recently published paper [2]. He reaches to the conclusion that vitamin D is not a tonic for bone and that, therefore, small amounts are needed to maintain bone health. Experimental investigation supporting this hypothesis showed that adequate intestinal calcium absorption is crucial for normal bone mass accrual and that 1,25(OH)2D signalling is crucial to secure this process, also during normal calcium intake [2]. The finding that the osteomalacia of the vitamin D receptor (VDR) knockout mouse is completely corrected by selective expression of VDR in the gut enterocytes is in line with previous observations [1, 2]. These data furthermore emphasize the relative importance of intestinal vitamin D receptor compared with skeletal VDR. Following these premises, the physiological role of VDR in bone in normal conditions should be better defined, also in light of the finding that selective knockout of this receptor in bone is paradoxically associated with an increase in bone mass [3]. Dr Reid postulates a critical effect of VDR in facilitating calcium absorption; it appears therefore intuitive that the most favourable meta-analyses, for example on the reduction of hip fractures, are those in which vitamin D is co-administered with calcium salts. We agree with the conclusion that vitamin D should be administered only to those who are insufficient or deficient, even though such thresholds are still an issue of discussion [4, 5]; similar to what happens in the field of other nutrients, a unique term should probably be used [6]. Concerning the three studies cited linking high doses of vitamin D to adverse effects on bone resorption and skeletal mass, we should observe that one of them used the active metabolite [1,25(OH)2D] which from a pharmacological point of view is different from its precursor [7]. The other studies utilized high doses of vitamin D [8, 9]; apart from possible biases [10], there is another study showing that the annual administration of vitamin D2 indeed decreased the incidence of fracture [11]. The statement that individuals living independently in the community and not dark skinned or veiled will not need supplements at all, is not universally applicable. Indeed, it is well known that sunlight is responsible for producing 80 % of the nutritional supply of vitamin D in the body and maximizes serum 25(OH)D levels only in summer and autumn. In Italy, for example, from late October till early March, we do not have enough UV light from the sun to make vitamin D in the skin; therefore, the possibility of being insufficient in the winter–spring season, it is not an unrealistic hypothesis. We do not entirely agree with Dr Reid’s suggestion that measuring serum 25(OH)D levels has no value [12–14]. Serum 25(OH)D is at present a satisfactory indicator of total body stores of vitamin D, even though problems with assay do exist [4]. To further complicate the issue, we still do not exactly know if the free fraction of 25(OH)D should be measured to obtain meaningful information with respect to what we presently know [15]. Therefore, because some issues are not fixed, we believe that a word of caution should be offered on the problems previously addressed. S. Minisola (&) C. Cipriani S. Piemonte J. Pepe Department of Internal Medicine and Medical Disciplines, ‘‘Sapienza’’ Rome University, Via del Policlinico 155, 00161 Rome, Italy e-mail: salvatore.minisola@uniroma1.it