Diagnosis and treatment of Paget's disease of bone: position paper from the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases (SIOMMMS).

INTRODUCTION: Paget's disease of bone is a focal skeletal disorder causing bone deformities and impairing bone quality. Despite the prevalence of asymptomatic cases is increasing, the progression of the disease can lead to invalidating complications that compromise the quality of life. Doubts on clinical and therapeutic management aspects exist, although beneficial effects of antiresorptive drugs, particularly bisphosphonates are known. However, limited information is available from randomized controlled trials on the prevention of disease complications so that somewhat contrasting positions about treatment indications between expert panels from the main scientific societies of metabolic bone diseases exist. This task force, composed by expert representatives appointed by the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases and members of the Italian Association of Paget's disease of bone, felt the necessity for more specific and up to date indications for an early diagnosis and clinical management. METHODS: Through selected key questions, we propose evidence-based recommendations for the diagnosis and treatment of the disease. In the lack of good evidence to support clear recommendations, available information from the literature together with expert opinion of the panel was used to provide suggestions for the clinical practice. RESULTS AND CONCLUSION: Description of the evidence quality and support of the strength of the statements was provided on each of the selected key questions. The diagnosis of PDB should be mainly based on symptoms and the typical biochemical and radiological features. While treatment is mandatory to all the symptomatic cases at diagnosis, less evidence is available on treatment indications in asymptomatic as well as in previously treated patients in the presence of biochemical recurrence. However, given the safety and long-term efficacy of potent intravenous bisphosphonates such as zoledronate, a suggestion to treat most if not all cases at the time of diagnosis was released.

Femoral bone mineral density at the time of hip fracture is higher in women with versus without type 2 diabetes mellitus: a cross-sectional study.

PURPOSE: To compare femoral bone mineral density (BMD) levels in hip-fracture women with versus without type 2 diabetes mellitus (T2DM). We hypothesized that BMD levels could be higher in the women with T2DM than in controls and we aimed to quantify the BMD discrepancy associated with the presence of T2DM. METHODS: At a median of 20 days after the occurrence of an original hip fracture due to fragility we measured BMD by dual-energy x-ray absorptiometry at the non-fractured femur. RESULTS: We studied 751 women with subacute hip fracture. Femoral BMD was significantly higher in the 111 women with T2DM than in the 640 without diabetes: mean T-score between-group difference was 0.50, (95% CI from 0.30 to 0.69, P < 0.001). The association between the presence of T2DM and femoral BMD persisted after adjustment for age, body mass index, hip-fracture type, neurologic diseases, parathyroid hormone, 25-hydroxyvitamin D and estimated glomerular filtration rate (P < 0.001). For a woman without versus with T2DM, the adjusted odds ratio to have a femoral BMD T-score below the threshold of - 2.5 was 2.13 (95% CI from 1.33 to 3.42, P = 0.002). CONCLUSIONS: Fragility fractures of the hip occurred in women with T2DM at a femoral BMD level higher than in control women. In the clinical assessment of fracture risk, we support the adjustment based on the 0.5 BMD T-score difference between women with and without T2DM, although further data from robust longitudinal studies is needed to validate the BMD-based adjustment of fracture risk estimation.

A single postdischarge telephone call by an occupational therapist does not reduce the risk of falling in women after hip fracture: a randomized controlled trial.

BACKGROUND: Post-discharge telephone calls to reinforce targeted recommendations for fall prevention have scarcely been investigated in hip-fracture survivors. AIM: To assess the effectiveness of a single telephone call by an occupational therapist in reducing the proportion of fallers (primary endpoint) and improving the adherence to targeted recommendations for fall prevention (secondary endpoint) after hospital discharge in hip-fracture women. DESIGN: Randomized controlled trial. SETTING: Post-acute rehabilitation hospital and community (post-discharge). POPULATION: We randomized 169 of 228 women with a fall-related fracture of the hip. Data for analyses were available for 153 women (78 from the intervention group and 75 controls). METHODS: All the women underwent a multidisciplinary program targeted at fall prevention during post-acute inpatient rehabilitation. Additionally, the intervention group received a telephone call by an occupational therapist to reinforce the targeted recommendations for fall prevention at a median of 18 days after discharge. The outcomes were assessed at a six-month follow-up. RESULTS: Eleven of the 78 women (14.1%) from the intervention group, and 10 of the 75 (13.3%) from the controls sustained at least one fall during the follow-up (relative risk=1.06; 95% CI from 0.48 to 2.34). The mean adherence to the recommendations for fall prevention was 75.1% in the intervention group and 71.2% in the controls (between group difference 3.9; 95% CI from -3.4 to 11.3; P=0.29). CONCLUSION: Our study does not support a post-discharge telephone call to reinforce the recommendations for fall prevention in hip-fracture women. CLINICAL REHABILITATION IMPACT: We contribute to elucidate one aspect of multidisciplinary fall-prevention strategies in hip-fracture survivors.

Safety profile of drugs used in the treatment of osteoporosis: a systematical review of the literature.

The range of osteoporosis treatments is increasingly large and, like any disease, the pharmacological management of patients should involve a risk/benefit evaluation to attain the greatest reduction in risk of fracture with the lowest incidence of adverse events. The aim of this review is to critically appraise the literature about the safety issues of the main pharmacological treatments of osteoporosis. This document is the result of a consensus of experts based on a systematic review of regulatory documents, randomized controlled trials, metaanalyses, pharmacovigilance surveys and case series related to possible adverse drug reactions to osteoporosis treatment with calcium and vitamin D supplements, bisphosphonates, strontium ranelate, selective estrogen receptor modulators, denosumab, and teriparatide. As expected, randomized controlled trials showed only the most common adverse events due to the samples size and the short observation time. Case series and observational studies are able to provide data about uncommon side effects, but in some cases a sure cause-effect relationship needs still to be confirmed. Consistently with methodological limitations, the newer drugs have a tolerance profile that has not been fully explored yet. Osteoporosis treatments showed an overall good tolerance profile with rare serious adverse events that, however, must be well known by the clinician who prescribes these drugs. The concern about possible adverse events should be weighed against the reduction of morbidity and mortality associated with a significant fracture risk reduction.

Which type of exercise therapy is effective after hip arthroplasty? A systematic review of randomized controlled trials.

BACKGROUND: Early multidisciplinary rehabilitation can improve the recovery after total hip arthroplasty (THA). However, optimal exercise therapy has not been defined. We aimed to answer the question: "Which type and/or timing of exercise therapy is effective following THA?" DESIGN: Systematic review. METHODS: We searched four databases: MEDLINE, PEDro, Cochrane Library, and Cinahl since January 2008 till December 2012. Literature before 2008 was not searched for, because it was previously analyzed by two systematic reviews. Eligible criteria for studies were: Randomized Controlled Trials (RCTs); English language; interventions on type and/or timing of physical exercise initiating after THA; outcome measures including at least one among impairment, activity, participation, quality of life, or length of stay in hospital. RESULTS: Eleven papers on nine RCTs were identified. Trial quality was mixed. PEDro scores ranged from four to eight. Exercise therapy varied greatly in type and timing. Each of the nine RCTs addressed a specific issue and overall the results were sparse. In the early postoperative phase favorable outcomes were due to ergometer cycling and maximal strength training. Inconclusive results were reported for aquatic exercises, bed exercises without external resistance or without its progressive increase according to the overload principle, and timing. In the late postoperative phase (> 8 weeks postoperatively) advantages were due to weight-bearing exercises. CONCLUSION: Insufficient evidence exists to build up a detailed evidence-based exercise protocol after THA. Sparse results from few RCTs support specific exercise types which should be added to the usual mobility training in THA patients.

Parathyroid hormone response to severe vitamin D deficiency is sex associated: an observational study of 571 hip fracture inpatients.

OBJECTIVES: To investigate the association between sex and parathyroid hormone response to severe vitamin D deficiency after hip fracture. DESIGN: Cross-sectional study. SETTING: Rehabilitation hospital in Italy. PARTICIPANTS: 571 consecutive inpatients with hip fracture and severe vitamin D deficiency (serum 25-hydroxyvitamin D < 12ng/ml), without hypercalcemia or estimated glomerular filtration rate (GFR) < 15ml/min. MEASUREMENTS: In each patient we assessed PTH (by two-site chemiluminescent enzyme-labelled immunometric assay), 25-hydroxyvitamin D (by immunoenzymatic assay), albumin-adjusted total calcium, phosphate, magnesium, and creatinine 21.3 ± 6.1 (mean ± SD) days after fracture occurrence. Functional level was assessed using the Barthel index. PTH response to vitamin D deficiency was classified as either secondary hyperparathyroidism (serum PTH >75pg/ml) or functional hypoparathyroidism, i.e., inappropriate normal levels of PTH (≤75pg/ml). RESULTS: Among the 571 patients, 336 (59%) had functional hypoparathyroidism, whereas 235 (41%) had secondary hyperparathyroidism. PTH status was significantly different between sexes (p=0.003): we found functional hypoparathyroidism in 61% of women and 43% of men (secondary hyperparathyroidism in 39% of women and 57% of men). The significance of the between-sex difference was maintained after adjustment for age, estimated GFR, phosphate, albumin-adjusted total calcium, albumin, Barthel index scores, 25-hydroxyvitamin D, and hip fracture type (either cervical or trochanteric). The adjusted odds ratio was 1.85 (95%CI from 1.09 to 3.13; p=0.023). CONCLUSIONS: Data shows that PTH response to vitamin D deficiency was sex-associated following a fracture of the hip. The higher prevalence of secondary hyperparathyroidism may play a role in the known prognostic disadvantage found in hip-fracture men.

Adherence to recommendations for fall prevention significantly affects the risk of falling after hip fracture: post-hoc analyses of a quasi-randomized controlled trial.

BACKGROUND: Few studies focused on fall prevention in hip-fracture survivors. AIM: To investigate the role of adherence to targeted recommendations on both home environment and behaviors in affecting the hazard of falling after a fall-related hip fracture. DESIGN: Post-hoc analysis of a quasi-randomized controlled trial. SETTING: Post-acute rehabilitation hospital. POPULATION: Ninety-five of 119 women living in the community with a fall-related fracture of the hip. METHODS: We assessed home hazard of falling and suggested targeted modifications of home environment and behaviors in activities of daily living to prevent falls during inpatient rehabilitation. Falls were recorded at a six-month follow-up during a pre-planned home visit. RESULTS: Nineteen of the 95 women sustained at least one fall during the six-month follow-up. Women with > 2 uncorrected risk factors had a significantly higher risk of falling than those with 0-2 risk factors; the odds ratio adjusted for four confounders was 4.58 (95%CI 1.472-4.250; P=0.009). Adherence to recommendations for fall prevention was negatively associated with fall risk. The adjusted odds ratio for a ten percent increase in adherence rate was 0.749 (95%CI 0.594-0.945; P=0.015). CONCLUSION: Uncorrected environmental and behavioral risk factors and poor adherence to targeted recommendations for fall prevention significantly predicted the risk of falling in community-dwelling women who sustained a fall-related hip fracture. CLINICAL REHABILITATION IMPACT: Fall-risk assessment should be performed during inpatient rehabilitation following a fall-related hip fracture. Improving adherence to targeted recommendations emerges as a major goal to prevent falls in hip-fracture survivors.

Rehabilitation after total hip arthroplasty: a systematic review of controlled trials on physical exercise programs.

Total hip arthroplasty (THA) has revolutionized the care of patients with end-stage joint disease, leading to pain relief, functional recovery, and substantial improvement in quality of life. However, long-term studies indicate persistence of impairment and functional limitation after THA, and the optimal rehabilitation protocols are largely unknown. The aim of this paper was to systematically review the controlled trials published on the effectiveness of physical exercise programs after THA. Nine studies were retrieved from MEDLINE and reviewed. Results show that the physical exercise protocols most frequently used after THA in the early postoperative phase are neither supported nor denied by clinical controlled trials. Convincing evidence for the effectiveness of single interventions in addition to usual exercise programs exists for each of the three following options: treadmill training with partial body-weight support, unilateral resistance training of the quadriceps muscle (operated side), and arm-interval exercises with an arm ergometer. In the late postoperative phase (operation interval > 8 weeks) exercise programs consistently improve both impairment and ability to function. Weight-bearing exercises with hip-abductor eccentric strengthening may be the crucial component of the late-phase protocols. Substantial limitations were found in the nine studies, including small sample size, patient selection, heterogeneity of outcome assessments, and potential sources of variability not investigated. Despite limitations, we conclude that three main suggestions emerge from controlled trials on physical exercise after THA: early postoperative protocols should include additive interventions whose effectiveness has been shown. Late postoperative programs are useful and should comprise weight-bearing exercises with hip-abductor eccentric strengthening.

Hip-fracture type does not affect the functional outcome after acute in-patient rehabilitation: a study of 684 elderly women.

AIM: To investigate differences in the functional outcome between women sustaining cervical or trochanteric fractures of the hip. METHODS: We studied 684 of 736 women admitted consecutively to a rehabilitation hospital in Italy because of their first hip fracture. Functional recovery was assessed by using Barthel index scores. Fractures were classified as either cervical (n=335) or trochanteric (n=349) on the basis of surgical and radiographic findings. RESULTS: After acute in-patient rehabilitation, women with trochanteric fracture had a significantly lower Barthel index score than women with cervical fracture (median values were 85 and 90 respectively, interquartile ranges were 25 and 30 respectively, P=0.001). Length of stay in the hospital was significantly longer in women with trochanteric fractures (median was 37 days vs 36 days; interquartile range was 10 days vs 8 days, P=0.018). However, the differences between the two groups were no longer significant after adjustment for eight variables that affect functional ability in the same population (i.e., age, pressure ulcers, cognitive impairment, neurologic impairment, infections during the length of stay, bone mineral density, body mass index, and Barthel index scores assessed before rehabilitation). Further-more, we found no significant differences in the change of Barthel index scores during rehabilitation and in Barthel index efficiency (change in the Barthel index score after rehabilitation divided by the length of stay in hospital) between the two groups of women. CONCLUSIONS: After adjustment for several confounders, we did not show significant differences in the functional outcome between women with cervical or trochanteric fracture of the hip.

Body composition and hip fracture type in elderly women.

Many observations support the view that there are significant differences between patients sustaining trochanteric fractures and those sustaining cervical fractures of the hip. Our aim was to evaluate the association between soft tissue composition (fat and lean compartments) and the type of hip fracture sustained. Of 120 consecutive women affected by their first hip fracture admitted to our rehabilitation hospital 102 were included in this cross-sectional study. Body composition was assessed by DXA. Body fat mass was lower in the women with trochanteric fracture than in those with cervical fracture (difference between groups: 2.86 kg; 95% CI 0.10-5.61 kg; p=0.042). The percentage of fat was 30.75+/-8.77 (mean+/-SD) versus 34.75+/-7.29 (difference between groups: 4.00; 95% CI 0.84-7.16; p=0.014). In contrast, no meaningful differences in body lean mass were shown between the two groups. Logistic multiple regression showed that fat mass was associated with the type of fracture independently of age, height, weight, time between fracture occurrence and DEXA assessment, comorbidity, number of drugs in use, lean mass and bone mineral content. The logistic regression results were similar when fat percentage was substituted for fat mass. The data show that fat but not lean body mass is associated with the type of hip fracture, contributing to the definition of the differences between patients sustaining cervical or trochanteric fractures. We stress the importance of distinguishing the two types of fracture when clinical or epidemiological studies related to body composition, including those regarding nutrition or physical exercise, are performed.

Fat body mass, leptin and femur bone mineral density in hip-fractured women.

Fat body mass (FBM) is a strong predictor of both bone mineral density (BMD) and risk of hip fracture, but the mechanisms responsible are not completely understood. We addressed whether leptin is the link between FBM and BMD in hip-fractured women. Sixty-two of 74 women with hip fractures were evaluated. Serum leptin was measured by radioimmunoassay, 23.4+/-9.1 days (mean+/-SD) after fracture occurrence. BMD and body composition were assessed by dual-energy X-ray absorptiometry (DXA). As expected, a positive linear correlation was found between FBM and both leptin (r=0.782; p<0.001) and femur BMD measured at five sites (r value ranging from 0.293 to 0.498 depending on the site of the femur BMD assessment, p<0.05). A positive correlation between leptin and BMD measured at the intertrochanteric area (r=0.259; p<0.05) but not at the other four sites was shown. At linear multiple regression [dependent variable = femur BMD; independent variables = age, weight, height, body mass index, fracture type, term fracture-DXA, Barthel index score, FBM, lean body mass, serum PTH, serum 25(OH)vitamin D and leptin], FBM was positively associated with BMD measured at all the five sites. The association between leptin and BMD was inverse and it was significant at four of the five sites of the BMD assessment. In conclusion, in a sample of hip-fractured women, the positive association between FBM and femur BMD was not explained by serum leptin. On the contrary, after adjustment for FBM and other confounding variables, an inverse association between leptin and BMD was found.

Femur bone mineral density, age and fracture type in 300 hip-fractured women.

BACKGROUND AND AIMS: Several studies showed that cervical and trochanteric hip fractures were associated with different levels of bone mineral density (BMD). Our aim was to investigate the association between femur BMD and hip fracture type at different ages. METHODS: We studied 300 postmenopausal women affected by their first hip fracture. 17 women could not undergo BMD measurement and were excluded. The fractures of the remaining 283 women were classified as either cervical (N=129) or trochanteric (N=154). The BMD of the unfractured femur was assessed by DXA. RESULTS: The women with trochanteric fracture had significantly lower BMD than those with cervical fracture at four sites: total proximal femur (p<0.001), trochanter (p<0.001), intertrochanteric area (p<0.01), and Ward's triangle (p<0.05). Logistic multiple regression showed that the association between hip fracture type and BMD was independent of age, weight, height, time between fracture occurrence and DXA assessment, number of concomitant diseases and number of drugs administered when BMD was evaluated at total proximal femur (p<0.001), trochanter (p<0.001), and intertrochanteric area (p<0.01). Age stratification showed that BMD was actually lower in the group with trochanteric fracture in the women aged 69 years and younger, and in those aged 80 years and older, but not in the intermediate age group (70-79 years). CONCLUSIONS: Data confirm previous reports showing that the two types of hip fractures are associated with different levels of BMD. Moreover, we show that the role played by BMD as a determinant of the hip fracture type varies with age.

Handgrip strength is an independent predictor of distal radius bone mineral density in postmenopausal women.

Several cross-sectional studies have reported a positive correlation between muscle strength and local bone mineral density. However, very few studies have evaluated the possible role of confounding variables, which may be substantial as both bone mineral density and muscle strength are multifactorial variables. We studied 140 postmenopausal women who underwent their first osteodensitometry in our hospital. Of these, 102 women affected neither by bone diseases apart from primary osteoporosis nor treated with drugs affecting bone mass were selected. Distal radius bone mineral density of the non-dominant arm was assessed by dual photon absorptiometry. Handgrip strength was measured by a handheld dynamometer. The following factors influencing bone mass were also considered: age, years since menopause, years of cyclic ovarian activity, body weight, body height, body mass index, and both calcium and alcohol dietary intake. Statistical evaluation was performed by stepwise multiple regression analysis. This showed that only two variables were independently related to bone mineral density: handgrip strength (which was the best bone density predictor among the studied independent variables) and years since menopause. R2 value was 0.43 (F=38.04, p < 0.001). All the other variables studied were not significantly related to bone density when the effects of both strength and years since menopause were considered. In conclusion, the data showed that handgrip strength was a strong independent predictor of distal radius bone mineral density in postmenopausal women. Clinical assessment of osteoporosis risk factors, including muscle strength, is recommended: although it is not an adequate substitute for bone densitometry, it can help clinicians to identify the risk groups at which to direct bone density measurement.

Dehydroepiandrosterone inhibits the growth of DMBA-induced rat mammary carcinoma via the androgen receptor.

Dehydroepiandrosterone (DHEA) exerts opposite effects on the growth of mammary carcinoma. A stimulatory effect is observed in absence of estrogens, due to interaction of DHEA metabolite(s) with the estrogen receptor (ER); by contrast, in presence of estrogens DHEA inhibits tumor growth. The mechanism underlying the latter DHEA effect, which might be related to activation of the androgen receptor (AR), is poorly understood. Focusing on this point, we measured over a 20 days period the areas of DMBA-induced mammary tumors in rats given DHEA and/or the anti-androgen flutamide (FLU). Results show that DHEA inhibitory effect on the growth of mammary carcinoma is no longer observed when the ARs are blocked by FLU. Data are consistent with an involvement of ARs in the inhibitory effect of DHEA.

Role of glucose-6-phosphate dehydrogenase inhibition in the antiproliferative effects of dehydroepiandrosterone on human breast cancer cells.

Epidemiological and experimental studies suggest that dehydroepiandrosterone (DHEA) exerts a protective effect against breast cancer. It has been proposed that the non-competitive inhibition of glucose-6-phosphate dehydrogenase (G6PD) contributes to DHEA antitumor action. We evaluated the effects of DHEA on G6PD activity and on the in vitro proliferation of two human breast cancer cell lines, MCF-7 (steroid receptor positive) and MDA-MB-231 (steroid receptor negative), in a serum-free assay. DHEA inhibition of G6PD was only found to occur at concentrations above 10 microM; at these high concentrations, the growth curve was parallel to the enzyme inhibition curve in both cell lines. In contrast, at concentrations in the in vivo breast tissue concentration range, neither cell growth nor enzyme activity was inhibited. The results failed to confirm DHEA's putative anti-tumor action on breast cancer through G6PD inhibition, as the enzyme blockade only becomes apparent at pharmacological concentrations of the steroid.

Dihydrotestosterone affects the growth of hormone-unresponsive breast cancer cells: an indirect action.

Cell to cell interaction, which plays a crucial role in breast cancer growth, may be regulated by steroid hormones. This study examined dihydrotestosterone (DHT) effects on the interaction between the steroid receptor positive MCF-7 and the steroid receptor negative MDA-MB-231 breast cancer cell lines. The growth of MDA-MB-231 cells was inhibited by medium conditioned by MCF-7 cells grown in presence of DHT but not by medium conditioned by MCF-7 cells grown in presence of both DHT and the antiandrogen hydroxyflutamide. Trypsin pretreatment of conditioned medium abolished its growth-inhibitory effect on hormone-unresponsive cells. DHT itself did not affect the growth of MDA-MB-231 cells when directly added to their culture medium. Data suggest that DHT stimulates, via the androgen receptor, the androgen-responsive breast cancer cells to produce a peptide factor(s) capable of inhibiting the growth of hormone-unresponsive cells.

Growth inhibition of DMBA-induced rat mammary carcinomas by the antiandrogen flutamide.

Antiandrogens have sporadically been reported to exert antitumor activities in both pre- and post-menopausal breast cancer. To explore the possibility of using the pure antiandrogen flutamide (FLU) in breast cancer therapy, rats bearing DMBA-induced mammary tumors were treated with FLU, dihydrotestosterone (DHT), or FLU plus DHT. FLU was administered orally, at doses comparable to those used in the treatment of prostate cancer patients. FLU-treated animals had a significantly smaller average tumor area than controls from day 11 up to the end of the experiment (day 20). A similar reduction of tumor growth was observed in rats given DHT and in those treated with DHT plus FLU. Plasma levels of LH, FSH, P, 17-OH P, E2 and DHEA measured at the end of experiment did not differ between treated animals and controls. Results demonstrate that the antiandrogen FLU and the full androgen DHT exert similar inhibitory effects on the growth of dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors. Moreover, data show that plasma steroids levels are unaffected by FLU treatment. This finding rules out any antitumor effect dependent on the reduction of adrenal and gonadal steroidosynthesis, and makes it appear more likely that androgen receptors are involved in the antiproliferative effect of FLU.