Extensive expertise in endocrinology: advances in the management of glucocorticoid-induced osteoporosis.

Osteoporosis is a common consequence of long-term oral glucocorticoid therapy and the resulting fractures cause significant morbidity. Bone loss occurs rapidly after initiation of glucocorticoid therapy; the accompanying increase in risk of fracture is dose-dependent and occurs within a few months of starting therapy. The adverse effects of glucocorticoids on bone are mediated by inhibition of bone formation accompanied by an early but transient increase in bone resorption, due both to direct and indirect effects on bone remodelling. Fracture risk assessment should be performed as soon as possible after long-term glucocorticoid therapy (≥3 months) is initiated. FRAX can be adjusted for the dose of prednisolone but does not currently take fracture site, recency, or number into account and therefore may underestimate fracture risk, particularly in individuals with morphometric vertebral fractures. Vertebral fracture assessment should therefore be regarded as a routine part of fracture risk estimation in individuals receiving long-term glucocorticoid therapy. Bone protective therapy should be started promptly in individuals at high-risk, together with calcium and vitamin D supplements. Bisphosphonates are generally regarded as first-line options on the grounds of their low cost, but anabolic therapy should be considered as an alternative first-line option in very high-risk individuals.

High Prevalence of Radiological Vertebral Fractures in Women on Thyroid-Stimulating Hormone-Suppressive Therapy for Thyroid Carcinoma.

Context: Bone loss and nonvertebral fractures have been reported in patients with differentiated thyroid carcinoma (DTC) undergoing thyroid-stimulating hormone (TSH) suppressive therapy. Radiological vertebral fractures (VFs) are an early and clinically crucial marker of bone fragility. Objective and Design: A cross-sectional study to evaluate the prevalence and determinants of radiological VFs in women receiving l-thyroxine (L-T4) therapy for DTC. Patients and Interventions: A total of 179 consecutive women (median age, 59 years; n = 178 postmenopausal) who had undergone thyroidectomy for DTC and were currently receiving L-T4 were evaluated for radiological VFs and bone mineral density (BMD). There were three TSH target levels [<0.5 mU/L, group 1 (n = 83); 0.5 to 1.0 mU/L, group 2 (n = 50); >1.0 mU/L, group 3 (n = 46)]. Results: VFs were found in 51 patients (28.5%), with significantly (P < 0.001) higher prevalence in group 1 (44.6%) as compared with group 2 (24.0%) and group 3 (4.3%). VF prevalence was not significantly different among patients in group 1 with normal BMD, osteopenia, or osteoporosis, whereas in groups 2 and 3, VFs were more frequent in patients with osteoporosis than in those with either osteopenia or normal BMD. In the whole population, VFs were significantly and independently associated with TSH level <1.0 mU/L; densitometric diagnosis of osteoporosis at lumbar spine, femoral neck, or total hip; age of patients; and duration of L-T4 therapy. Conclusion: The prevalence of VFs was high in women with DTC who were undergoing long-term, suppressive L-T4 therapy.

Morphometric vertebral fractures in breast cancer patients treated with adjuvant aromatase inhibitor therapy: A cross-sectional study.

BACKGROUND: The impact of long-term adjuvant therapy with aromatase inhibitors (AIs) on vertebral fracture (VF) risk is still unclear. OBJECTIVE: In this cross-sectional study, we explored the prevalence and determinants of VFs in breast cancer (BC) patients before and during AI therapy. Each woman underwent a dual-energy X-ray absorptiometry (DXA) to evaluate bone mineral density (BMD) and identify VFs by a quantitative morphometric approach. Blood samples were collected to measure serum hormone and calcium levels. RESULTS: We consecutively included 263 postmenopausal women with hormone receptor-positive early BC. One-hundred-sixty-nine women were AI-naïve, and 94 were AI-treated. AI-treated patients had lower BMD at total hip (p=0.01) and lumbar spine (p=0.03), higher serum vitamin D (p<0.001) and parathyroid hormone (p=0.006) values as compared to AI-naïve patients. The prevalence of VFs was 18.9% in AI-naïve patients, and 31.2% in those assessed during AI therapy (odds ratio 1.90, 95% CI 1.1-3.5, p=0.03). In AI-naïve patients, VFs were associated with older age (p=0.002) and lower BMD values at femoral neck (p=0.04) and total hip (p=0.007), whereas VFs occurred without association with any parameter analyzed in AI-treated patients. In AI-treated group, the prevalence of VFs was not significantly different between patients with osteoporosis and those with normal BMD (36.7% vs. 20.0%; p=0.31). CONCLUSIONS: In women with early BC, AI therapy is associated with high prevalence of radiological VFs, which were shown to be independent of BMD values during the adjuvant treatment. These findings may be clinically relevant since they may lead to a change in management of AI-induced skeletal fragility. Specifically, the results of this study provide a rationale for performing a morphometric evaluation of VFs in all women undergoing treatment with AIs.

Fracture risk in oral glucocorticoid users: a Bayesian meta-regression leveraging control arms of osteoporosis clinical trials.

UNLABELLED: Little data exist on the frequency of fracture among oral glucocorticoid users. We examined the effect of oral glucocorticoids on fracture incidence using data from randomized controlled trials. Patients starting glucocorticoids had a higher probability of fracture and decline in bone mineral density compared to chronic glucocorticoid users. INTRODUCTION: Oral glucocorticoids (GCs) are the leading cause of secondary osteoporosis. However, there have been few studies that quantify the rate of fracture among GC users. We sought to provide a pooled estimate of fracture risk from randomized controlled trials (RCTs) of GC-treated patients. METHODS: We updated a MEDLINE search published by the American College of Rheumatology through to March 2015 and identified RCTs of osteoporosis therapies that reported fracture and bone mineral density (BMD) among oral GC users. We restricted the analysis to placebo or control arms. RCT arms were stratified by GC exposure at enrolment to GC initiators (≤6 months) and chronic GC users (>6 months). Bayesian meta-regression was used to estimate the annual probability of vertebral fracture (primary), non-vertebral fracture and percentage change in lumbar spine and femoral neck BMD. RESULTS: The annual incidence of vertebral and non-vertebral fracture was 5.1 % (95 % CrI = 2.8-8.2) and 2.5 % (95 % CrI = 1.2--4.2) among GC initiators, and 3.2 % (95 % CrI = 1.8-5.0) and 3.0 % (95 % CrI = 0.8-5.9) among chronic GC users. Our meta-regression identified a non-significant effect of group-level variables (mean age, mean BMD, mean GC daily dose, patients with previous vertebral fractures, proportion of women and adjuvant used) on vertebral fracture rate. CONCLUSION: Our study found higher vertebral fracture incidence among GC initiators, yet a relative decline in fracture incidence with longer exposure. Our findings suggest that fracture incidence among oral GC users may be more common than previously estimated. Optimizing GC-induced osteoporosis management during early exposure to GC is essential to prevent fractures.

Impact of androgen suppression and zoledronic acid on bone mineral density and fractures in the Trans-Tasman Radiation Oncology Group (TROG) 03.04 Randomised Androgen Deprivation and Radiotherapy (RADAR) randomized controlled trial for locally advanced prostate cancer.

OBJECTIVE: To study the influence of adjuvant androgen suppression and bisphosphonates on incident vertebral and non-spinal fracture rates and bone mineral density (BMD) in men with locally advanced prostate cancer. PATIENTS AND METHODS: Between 2003 and 2007, 1071 men with locally advanced prostate cancer were randomly allocated, using a 2 × 2 trial design, to 6 months i.m. leuprorelin (androgen suppression [AS]) before radiotherapy alone ± 12 months additional leuprorelin ± 18 months zoledronic acid (ZdA), commencing at randomization. The main endpoint was incident thoraco-lumbar vertebral fractures, which were assessed radiographically at randomization and at 3 years, then reassessed by centralized review. Subsidiary endpoints included incident non-spinal fractures, which were documented throughout follow-up, and BMD, which was measured in 222 subjects at baseline, 2 years and 4 years. RESULTS: Incident vertebral fractures at 3 years were observed in 132 subjects. Their occurrence was not increased by 18 months' AS, nor reduced by ZdA. Incident non-spinal fractures occurred in 72 subjects and were significantly related to AS duration but not to ZdA. Osteopenia and osteoporosis prevalence rates at baseline were 23.4 and 1.4%, respectively, at the hip. Treatment for 6 and 18 months with AS caused significant reductions in hip BMD at 2 and 4 years (P < 0.01) and ZdA prevented these losses at both time points. CONCLUSION: In an AS-naïve population, 18 months of ZdA treatment prevented the sustained BMD losses caused by 18 months of AS treatment; however, the study power was insufficient to show that AS duration or ZdA influenced vertebral fracture rates.

Bleeding, vertebral fractures and vascular calcifications in patients treated with warfarin: hope for lower risks with alternative therapies.

Anticoagulant therapy in patients with atrial fibrillation requires careful evaluation because its benefits i.e. prevention of thromboembolism, must be greater than the risk of bleeding. Patients at higher risk of thrombosis are evaluated through specific scores, such as the CHA(2)DS(2)VASc, coupled with scoring systems for assessing bleeding risks, such as the HAS-BLED score. In addition to bleeding, other risks have been associated with the use of warfarin, including an increased susceptibility to vascular calcifications and fractures caused by a reduction in the levels of vitamin K dependent carboxylated enzymes, matrix Gla-protein (MGP) and bone Gla-protein or osteocalcin (BGP). In fact, while on one side warfarin is used to prevent embolism, on the other hand acting as a vitamin K antagonist it blocks the inhibitory effect of MGP on vascular calcification. Similarly, patients treated with warfarin carry a greater risk of developing osteoporosis and fractures, due to reduced BGP activity. Recently, a new generation of anticoagulant drugs has been developed, such as dabigatran, a direct thrombin inhibitor, and rivaroxaban, a direct factor-Xa inhibitor. They offer an interesting alternative to warfarin, because they do not require frequent blood tests for monitoring while offering similar results in terms of efficacy. Lacking the inhibitory effect on the vitamin K cycle, the consequent side effects can be avoided. If, compared to warfarin treated patients, a lower incidence of vascular calcifications and fractures will be demonstrated, the advantages over warfarin may be even greater, leading to further benefits in terms of morbidity and mortality.

Glucocorticoid-related osteoporotic fractures.

INTRODUCTION: This study was conducted to evaluate the prevalence of fractures secondary to steroid use. METHODS: A total of 165 patients (100 male and 65 female) who received glucocorticoid therapy at a dose of 7.5 mg or more, or its equivalent, for more than six months were identified from July 1, 2007 to December 30, 2007. Data extracted included age, gender, dose of glucocorticoid, concomitant diseases, the use of anti-resorptive therapy, calcium and vitamin D supplementation, and the results of bone mineral density (BMD) tests, if performed. Any fragility fractures, the site involved and the treatment administered were also recorded. The data was entered and analysed using the Statistical Package for the Social Sciences. RESULTS: 140 patients had no fractures while 25 (15.2 percent) sustained an osteoporotic fracture. The age (p-value less than 0.5), dose of steroids (p-value less than 0.001) and duration of glucocorticoid therapy (p-value less than 0.001) were significantly higher among patients who sustained fractures. Of these, 12 were male and 13 were female. None of the patients in both groups was started on antiresorptive therapy. The dosage of glucocorticoids was higher among women than men (11.5 versus 24.5 mg/day, p-value is 0.05). The commonest sites of osteoporotic fracture were the spine (44 percent) and proximal femur (24 percent). Eight out of 11 patients had more than one vertebra involved. CONCLUSION: Fractures due to steroid-induced osteoporosis could have been prevented if appropriate measures were taken.

Notable difference between the development of vertebral fracture and osteonecrosis of the femoral head in patients treated with high-dose glucocorticoids for systemic rheumatic diseases.

OBJECTIVE: Vertebral fracture (VF) and osteonecrosis of the femoral head (OFH) are serious concerns in patients with rheumatic diseases treated with high-dose glucocorticoids (GCs). We comparatively examined the risk factors of VF and OFH in patients who had recently received high-dose GC therapy. PATIENTS AND METHODS: Patients with rheumatic diseases receiving GCs (> or =0.5 mg/kg/day for prednisolone equivalent) within the past 2 months were enrolled in this study, and treated with 200 mg/day of etidronate cyclically. The bone mineral density (BMD) of the lumbar spine (L2-4) was examined by QDR2000. OFH was evaluated by magnetic resonance imaging (MRI). [ClinicalTrials.gov identifier: NCT00679978]. RESULTS: Forty-four patients completed the 2-year study including annual X-rays and the BMD analysis. MRI evaluation at entry and 2 years was performed in 41 patients. The BMD values with anteroposterior (AP) and lateral views decreased by 6.4% and 9.7%, respectively, in the first year, but were stable in the second year. Eleven patients developed VF and 9 patients developed OFH. The risk factors for VF included previous VF and a low BMD value (T score<-1.5) of AP view at baseline with an odds ratio (OR) of 14.9 (95%CI 2.9-76.4), while the risk factor for OFH was a recent maximum GC dosage (>1.2 mg/kg/day versus< or =; OR=7.7, 95%CI 1.3-45.5) and a decrease in BMD value of lateral view (>15% versus< or =; OR=6.7, 95% CI 1.2-36.1) in the first year. CONCLUSION: The development of VF relies on the predisposing factors, while that of OFH depends on the response to high-dose GC therapy.

Superiority of alfacalcidol over plain vitamin D in the treatment of glucocorticoid-induced osteoporosis.

Supplementation therapy with plain vitamin D plus calcium is in general regarded as effective prevention or first-step treatment of glucocorticoid-induced osteoporosis (GIOP). The aim of our study was to compare the therapeutic efficacy of the D-hormone analog alfacalcidol with plain vitamin D in patients with established GIOP with or without vertebral fractures. Patients on long-term glucocorticoid (GC) therapy were included as matched pairs to receive randomly either 1 microg alfacalcidol plus 500 mg calcium per day (group A, n=103) or 1000 IU vitamin D3 plus 500 mg calcium (group B, n=101). The two groups were well matched in terms of mean age, sex ratio, mean height and weight, daily dosage, and duration of GC therapy, and the percentages of the three underlying diseases included chronic obstructive pulmonary disease, rheumatoid arthritis, and polymyalgia rheumatica. The baseline mean bone mineral density (BMD) values at the lumbar spine for the two groups were -3.26 (alfacalcidol) and -3.25 (vitamin D(3)) and, at the femoral neck, -2.81 and -2.84, respectively (T scores). Rates of prevalent vertebral and nonvertebral fractures did not differ between groups. During the 3-year study, we observed a median percentage increase of BMD at the lumbar spine of 2.4% in group A and a loss of 0.8% in group B ( P<0.0001). There also was a larger median increase at the femoral neck in group A (1.2%) than in group B (0.8%) ( P<0.006). The 3-year rates of patients with at least one new vertebral fracture were 9.7% among those assigned to the alfacalcidol group and 24.8% in the vitamin D group (risk reduction 0.61, 95% CI 0.24-0.81, P=0.005). The 3-year rates of patients with at least one new nonvertebral fracture were 15% in the alfacalcidol group and 25% in the vitamin D group (risk reduction 0.41, 95% CI 0.06-0.68, P=0.081). The 3-year rates of patients with at least one new fracture of any kind were 19.4% among those treated with alfacalcidol and 40.65% with vitamin D (risk reduction 0.52, 95% CI 0.25-0.71, P=0.001). In accordance with the observed fracture rates, the alfacalcidol group showed a substantially larger decrease in back pain than the plain vitamin D group ( P<0.0001). Generally, side effects in both groups were mild, and only three patients in the alfacalcidol group and two in the vitamin D group had moderate hypercalcemia. We conclude that alfacalcidol plus calcium is highly superior to plain vitamin D3 plus calcium in the treatment of established GIOP.

A cost effectiveness analysis of calcium and vitamin D supplementation, etidronate, and alendronate in the prevention of vertebral fractures in women treated with glucocorticoids.

OBJECTIVE: To assess the relative costs and benefits of calcium and vitamin D supplements, cyclic etidronate, or alendronate in the prevention of vertebral fractures for women and with normal bone density and osteopenia who are about to initiate moderate dose glucocorticoid treatment. METHODS: Using a decision analysis model, we evaluated the following patients: 4 hypothetical cohorts: 30-yr-old women with normal lumbar spine (LS) bone mineral density (BMD) (t score = 0), 50-yr-old women with borderline osteopenia (t score = -1), 60-yr-old women with moderate osteopenia (t score = -1.5), and 70-yr-old women with severe osteopenia (t score = -2) treated with a mean prednisone dose of 10 mg/day for one year. The main outcomes included the development of vertebral fractures 10 years after glucocorticoid treatment and at age 80 (life-time risk) and direct and indirect costs. RESULTS: At 10 years, calcium and vitamin D supplements decreased fracture rates by 30-50% at a minimal cost (US$800 or less per vertebral fracture avoided) or at a cost saving compared to no treatment for women with osteopenia (t score -1 to -2). Etidronate and alendronate are most cost effective in women with borderline osteoporosis (t scores of -1.5 and -2) in the 10 year analysis. In the life-time analysis, calcium and vitamin D treatment yielded a cost savings compared to no treatment for all groups with osteopenia. Etidronate decreased fracture rates further in all groups at a cost of less than $2,000 per fracture prevented. Alendronate reduced the fracture risk further at cost of $3,000-7,000 per fracture avoided. CONCLUSION: Calcium and vitamin D supplements and low cost bisphosphonate regimens such as cyclic etidronate decrease the life-time vertebral fracture risk at acceptable costs and should be considered when initiating glucocorticoid treatment for women who do not have osteoporosis.

Risedronate increases bone density and reduces vertebral fracture risk within one year in men on corticosteroid therapy.

Limited information is available on the effect of bisphosphonates in men receiving corticosteroid therapy. We studied 184 men among the patients enrolled in two, double-blind, placebo-controlled, 1-year studies with similar protocols. The studies evaluated the effects of risedronate in patients beginning corticosteroid treatment at a dose of at least 7.5 mg per day of prednisone or equivalent (prevention study) or continuing long-term treatment of corticosteroid at that dose (treatment study). The men received either placebo or risedronate (2.5 mg or 5 mg) daily, along with calcium supplementation (500-1000 mg). Endpoints included differences in bone mineral density (BMD) at the lumbar spine, femoral neck, and femoral trochanter, assessment of vertebral fractures, changes in biochemical markers of bone turnover, and overall safety. In the treatment study, risedronate 5 mg significantly (P < 0.01) increased lumbar spine BMD by 4.8% at the lumbar spine, 2.1% at the femoral neck, and 2.6% at the femoral trochanter compared with baseline values. In the prevention study, bone loss was prevented with risedronate 5 mg; in the placebo group, BMD decreased significantly (P < 0.01) by 3.4%, 3.3%, and 3.4% in the lumbar spine, femoral neck, and trochanter, respectively, at 1 year. The differences between risedronate 5 mg and placebo groups were significant at all skeletal sites in the prevention study (P < 0.01) and at the lumbar spine in the treatment study (P < 0.001). The 2.5 mg dose also had a positive effect on BMD, although of a lesser magnitude than the 5 mg dose. When the data from the two studies were combined, the incidence of vertebral fractures decreased 82.4% (95% confidence interval, 36.6%-95.1%) in the pooled risedronate groups compared with placebo (P = 0.008). Risedronate was well tolerated in men, with a similar incidence of upper gastrointestinal adverse events in the placebo and treatment groups. Daily treatment with risedronate increases bone density and decreases vertebral fracture risk within 1 year in men receiving corticosteroid therapy.

Oral glucocorticoid-induced fall in cortical bone volume and density in postmenopausal asthmatic patients.

Despite a deepening understanding of the influence of glucocorticoids (GC) on trabecular bone, little is known about GC-induced cortical bone loss. To elucidate the mechanism of GC-induced loss of cortical bone strength with particular reference to cortical bone loss, changes in cortical density, relative cortical volume, and the Strength Strain Index (SSI) based on biomechanical analyses of the geographic distribution of cortical bone material were measured. These parameters were compared, using peripheral quantitative computed tomography (pQCT), among the following age-matched groups: 68 postmenopausal asthmatic patients receiving high-dose oral GC in addition to inhaled GC (oral GC group), 68 postmenopausal asthmatic patients receiving only inhaled GC (inhaled GC group) and 69 postmenopausal controls without asthma or GC therapy (control group). Cortical bone mineral density (BMD) was measured, relative cortical volume was obtained by dividing the cortical area by the total bone area using pQCT (Stratec XCT960), and the Strength Strain Index (SSI) was calculated in the radius based on the density distribution around the axis. Spinal fracture was assessed on lateral radiographs. The number of vertebral fractures per patient correlated highly with cortical BMD, relative cortical volume and SSI values at the radius. The number of vertebral fractures per patient and the number of patients with fracture were similar between the control and inhaled GC group, both being significantly lower than those in the oral GC group. Total BMD, trabecular BMD, cortical BMD, relative cortical volume and SSI were similar between the first two, being significantly higher than in the last group. The slopes of cortical volume-density relationship, however, were identical among the three groups, indicating the persistence of cortical bone remodeling and a similar degree of calcification regardless of GC administration.

Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy.

Men and women (n = 518) receiving moderate-to-high doses of corticosteroids were enrolled in two studies with similar protocols and randomly assigned to receive either placebo or risedronate (2.5 or 5 mg) for 1 year. All patients received daily calcium supplementation (500-1000 mg), and most also received supplemental vitamin D (400 IU). The primary endpoint was the difference between the placebo and active groups in lumbar spine bone mineral density (BMD) at 1 year; changes in BMD at other sites, biochemical markers of bone turnover, and the incidence of vertebral fractures were also assessed. In the overall population, the mean (SE) lumbar spine BMD increased 1.9 +/- 0.38% from baseline in the risedronate 5 mg group (P < 0.001) and decreased 1.0 +/- 0.4% in the placebo group (P = 0. 005). BMD at the femoral neck, trochanter, and distal radius increased or was maintained with risedronate 5 mg treatment, but decreased in the placebo group. Midshaft radius BMD did not change significantly in either treatment group. The difference in BMD between the risedronate 5 mg and placebo groups was significant at all skeletal sites (P < 0.05) except the midshaft radius at 1 year. The 2.5 mg dose also had a positive effect on BMD, although of a lesser magnitude than that seen with risedronate 5 mg. A significant reduction of 70% in vertebral fracture risk was observed in the risedronate 5 mg group compared with the placebo group (P = 0.01). Risedronate was efficacious in both men and women, irrespective of underlying disease and duration of corticosteroid therapy, and had a favorable safety profile, with a similar incidence of upper gastrointestinal adverse events in the placebo and active treatment groups. Daily treatment with risedronate 5 mg significantly increases BMD and decreases vertebral fracture risk in patients receiving moderate-to-high doses of corticosteroid therapy.

[Therapy of glucocorticoid-induced osteoporosis with alfacalcidol/calcium and vitamin D/calcium]. / Therapie der Glucocorticoid-induzierten Osteoporose mit Alfacalcidol/Kalzium und Vitamin D/Kalzium.

Calcium/vitamin D supplementation is generally used as a first step treatment of glucocorticoid-induced osteoporosis (GIOP). The aim of this trial was to compare the efficacy of the D-hormone alfacalcidol with plain vitamin D in patients with established GIOP with or without vertebral fractures. Patients on long-term glucocorticoid-therapy were treated either with 1 microgram alfacalcidol plus 5000 mg calcium (group A: n = 43) or with 1000 IU vitamin D plus 500 mg calcium (group B: n = 42). The two groups were not different in respect to initial characteristics such as age, sex distribution, concomittant diseases, bone mineral density (mean T-score values at lumbar spine and femoral neck: -3.29 and -3.25 resp.), and in the number of prevalent vertebral and non-vertebral fractures. During the 3 years of treatment we found a significant increase in lumbar spine density in group A (+2.0%, p < 0.0001), while no significant changes could be documented in group B at both measuring sites. After 3 years 12 new vertebral fractures had occurred in 10 patients of group A and 21 in 17 patients in group B (ns). Correspondingly we registered a significant decrease of back pain only in group A (p < 0.0001). We conclude that alfacalcidol treatment in superior to plain vitamin D in GIOP.