Carolina Aguiar Moreira

Effects of Abaloparatide-SC (BA058) on bone histology and histomorphometry: The ACTIVE phase 3 trial.

There are a number of effective treatments for osteoporosis but most are in the antiresorptive class of compounds. Abaloparatide-SC is a new osteoanabolic agent, which increased bone mineral density and lowered the risk of osteoporosis-related fractures in the phase 3 ACTIVE trial. The objective of this report is to describe the effects of abaloparatide-SC 80μg on bone histology and histomorphometry in iliac crest bone biopsies from this trial in which participants were randomized to receive blinded daily subcutaneous injections of placebo or abaloparatide-SC 80μg/d or open-label teriparatide 20μg/d for 18months. Iliac crest bone biopsies were obtained between 12 and 18months. Qualitative histological analysis of biopsies from abaloparatide-SC-treated patients revealed normal bone microarchitecture without evidence of adverse effects on mineralization or on the formation of normal lamellar bone. There were no bone marrow abnormalities, marrow fibrosis nor was there presence of excess osteoid or woven bone. There were few significant differences among the three treatment groups in a standard panel of static and dynamic histomorphometric indices. The mineral apposition rate was higher in the teriparatide-treated group than in the placebo-treated group. The eroded surface was lower in the abaloparatide-SC-treated group than in the placebo-treated group. Cortical porosity was higher in both the abaloparatide-SC- and the teriparatide-treated groups than in the placebo-treated group. We conclude that histological and histomorphometric analysis of iliac crest bone biopsies from subjects who were treated for up to 18months with abaloparatide-SC showed no evidence of concern for bone safety. TRIAL REGISTRATION ClinicalTrials.gov number NCT01343004.

Sarcopenia in COPD: relationship with COPD severity and prognosis

Objective: To evaluate the prevalence of sarcopenia in COPD patients, as well as to determine whether sarcopenia correlates with the severity and prognosis of COPD. Methods: A cross-sectional study with COPD patients followed at the pulmonary outpatient clinic of our institution. The patients underwent dual-energy X-ray absorptiometry. The diagnosis of sarcopenia was made on the basis of the skeletal muscle index, defined as appendicular lean mass/height2 only for low-weight subjects and adjusted for fat mass in normal/overweight subjects. Disease severity (COPD stage) was evaluated with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. The degree of obstruction and prognosis were determined by the Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity (BODE) index. Results: We recruited 91 patients (50 females), with a mean age of 67.4 ± 8.7 years and a mean BMI of 25.8 ± 6.1 kg/m2. Sarcopenia was observed in 36 (39.6%) of the patients, with no differences related to gender, age, or smoking status. Sarcopenia was not associated with the GOLD stage or with FEV1 (used as an indicator of the degree of obstruction). The BMI, percentage of body fat, and total lean mass were lower in the patients with sarcopenia than in those without (p < 0.001). Sarcopenia was more prevalent among the patients in BODE quartile 3 or 4 than among those in BODE quartile 1 or 2 (p = 0.009). The multivariate analysis showed that the BODE quartile was significantly associated with sarcopenia, regardless of age, gender, smoking status, and GOLD stage. Conclusions: In COPD patients, sarcopenia appears to be associated with unfavorable changes in body composition and with a poor prognosis.

Subtle changes in bone mineralization density distribution in most severely affected patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is associated with low aBMD as measured by DXA and altered microstructure as assessed by bone histomorphometry and microcomputed tomography. Knowledge of bone matrix mineralization is lacking in COPD. Using quantitative backscatter electron imaging (qBEI), we assessed cancellous (Cn.) and cortical (Ct.) bone mineralization density distribution (BMDD) in 19 postmenopausal women (62.1 ± 7.3 years of age) with COPD. Eight had sustained fragility fractures, and 13 had received treatment with inhaled glucocorticoids. The BMDD outcomes from the patients were compared with healthy reference data and were correlated with previous clinical and histomorphometric findings. In general, the BMDD outcomes for the patients were not significantly different from the reference data. Neither the subgroups of with or without fragility fractures or of who did or did not receive inhaled glucocorticoid treatment, showed differences in BMDD. However, subgroup comparison according to severity revealed 10% decreased cancellous mineralization heterogeneity (Cn.CaWidth) for the most severely affected compared with less affected patients (p=0.042) and compared with healthy premenopausal controls (p=0.021). BMDD parameters were highly correlated with histomorphometric cancellous bone volume (BV/TV) and formation indices: mean degree of mineralization (Cn.CaMean) versus BV/TV (r=0.58, p=0.009), and Cn.CaMean and Ct.CaMean versus bone formation rate (BFR/BS) (r=-0.71, p<0.001). In particular, those with lower BV/TV (<50th percentile) had significantly lower Cn.CaMean (p=0.037) and higher Cn.CaLow (p=0.020) compared with those with higher (>50th percentile) BV/TV. The normality in most of the BMDD parameters and bone formation rates as well as the significant correlations between them suggests unaffected mineralization processes in COPD. Our findings also indicate no significant negative effect of treatment with inhaled glucocorticoids on the bone mineralization pattern. However, the observed concomitant occurrence of relatively lower bone volumes with lower bone matrix mineralization will both contribute to the reduced aBMD in some patients with COPD.

Skeletal Implications of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is associated with numerous comorbidities, among which osteoporosis is of high significance. Low bone mass and the occurrence of fragility fractures is a common finding in patients with COPD. Typical risk factors related directly or indirectly to these skeletal complications include systemic inflammation, tobacco smoking, vitamin D deficiency, and treatment with oral or inhaled corticosteroids. In particular, treatment with glucocorticoids appears to be a strong contributor to bone changes in COPD, but does not fully account for all skeletal complications. Additional to the effects of COPD on bone mass, there is evidence for COPD-related changes in bone microstructure and material properties. This review summarizes the clinical outcomes of low bone mass and increased fracture risk, and reports on recent observations in bone tissue and material in COPD patients.

Stress Fractures: Concepts and Therapeutics

Context: Stress fractures are repetitive use injuries in which recurrent strains lead to material fatigue and microarchitectural discontinuities. They account for up to 20% of athletic injuries, more often in women and in the setting of track-and-field events. In women, menstrual disturbances, low body mass index, low energy intake, and sometimes low bone mass, may be contributing factors. There are no standard protocols for evaluation or management of stress fractures. Evidence Acquisition: Available literature published in English was retrieved using the following terms: stress fractures; fractures; osteoporosis, athletes, premenopausal women, and athletic triad; through PubMed. Reviews, original reports, and case reports were all included. Evidence Synthesis: Despite lack of consistency among the publications, a phenotype emerges, namely of individuals whose bone mineral density is reduced along with low intake of dietary calcium and low circulating levels of 25-hydroxy vitamin D. Limited experience suggests that calcium and vitamin D supplementation might be helpful. Bisphosphonates or teriparatide may accelerate fracture healing in special circumstances. Conclusions: Most individuals who experience a stress fracture are young and healthy and do not appear to have an underlying metabolic bone disease. On the other hand, the presence of low bone mass and hormonal disturbances in some afflicted individuals might identify a cohort who needs endocrinological attention. Prospective, well-designed studies of stress fractures are needed to elucidate further underlying pathophysiological elements that predispose such individuals. Guidelines for prevention and treatment may follow from such well-controlled studies.

Fragility Fracture Incidence in Chronic Obstructive Pulmonary Disease (COPD) Patients Associates with Nanoporosity, Mineral/Matrix Ratio, and Pyridinoline Content at Actively Bone Forming Trabecular Surfaces.

Chronic obstructive pulmonary disease (COPD) is associated with low areal bone mineral density (aBMD) by dual‐energy X‐ray absorptiometry (DXA) and altered microstructure by bone histomorphometry and micro‐computed tomography. Nevertheless, not all COPD patients sustain fragility fractures. In the present study, we used Raman microspectroscopic analysis to determine bone compositional properties at actively forming trabecular surfaces (based on double fluorescent labels) in iliac crest biopsies from 19 postmenopausal COPD patients (aged 62.1 ± 7.3 years). Additionally, we analyzed trabecular geometrical centers, representing tissue much older than the forming surfaces. Eight of the patients had sustained fragility fractures, and 13 had received treatment with inhaled glucocorticoids. None of the patients had taken oral glucocorticoids. The monitored parameters were mineral/matrix ratio (MM), nanoporosity, and relative glycosaminoglycan (GAG), lipid, and pyridinoline contents (PYD). There were no significant differences between the glucocorticoid‐treated patients and those who did not receive any. On the other hand, COPD patients sustaining fragility fractures had significantly lower nanoporosity and higher MM and PYD values compared with COPD patients without fragility fractures. To the best of our knowledge, this is the first study to discriminate between fracture and non‐fracture COPD patients based on differences in the material properties of bone matrix. Given that these bone material compositional differences are evident close to the cement line (a major bone interface), they may contribute to the inferior bone toughness and coupled with the lower lumbar spine bone mineral density values result in the fragility fractures prevalent in these patients.

New insights on diabetes and bone metabolism

Diabetes mellitus is a common chronic metabolic disease worldwide whose prevalence has increased during the last decades. Besides its more commonly recognized complications, such as macrovascular disease, retinopathy, nephropathy and neuropathy, diabetes related bone disease has gained growing attention. Diabetic patients are more prone to fracture than the general population as well as to low turnover bone disease in the chronic kidney disease setting. In this review, we discuss the relationship between diabetes and bone as well as the pathogenesis of bone fragility in T2D.

Use of pamidronate for osteoporosis treatment in public health care in Brazil

PURPOSE The use of bisphosphonates for osteoporosis is effective in reducing the risk of fractures. However, oral formulations are sometimes not well tolerated or are contraindicated. Due to its availability in Brazilian public health system, pamidronate is frequently prescribed for osteoporosis, despite the lack of studies demonstrating its anti-fracture efficacy and the absence of FDA or EMEA approval for this purpose. The aim of this study was to evaluate the bone mineral density (BMD) response to pamidronate in a group of women with osteoporosis in a tertiary care hospital. PATIENTS AND METHODS The medical records of women with osteoporosis who received pamidronate for up to two years of treatment were reviewed. Patients were stratified at high or intermediate risk of fracture. RESULTS A total of 70 women were in treatment with pamidronate. Among them, 74% were at high risk of fracture. A significant gain in spine BMD after 24 months of treatment was observed (p=0.012). There was no difference between the groups of high and not high risk of fracture. At the femur, no significant increase in BMD was present, though, a strong negative correlation with high PTH levels (r=-0.61; p=0.003) was seen. In the multivariate analysis BMI at 12 months had impact in the response to the treatment. CONCLUSION The intravenous pamidronate in a group of postmenopausal women with predominant high risk of fracture promoted an isolated gain in the spine BMD, even though, clinical randomized trials are needed to confirm its anti-fracture efficacy.

Hypoparathyroidism and pseudohypoparathyroidism: etiology, laboratory features and complications

Objectives To identify a clinical profile and laboratory findings of a cohort of hypoparathyroidism patients and determine the prevalence and predictors for renal abnormalities. Materials and methods Data from medical records of five different visits were obtained, focusing on therapeutic doses of calcium and vitamin D, on laboratory tests and renal ultrasonography (USG). Results Fifty-five patients were identified, 42 females and 13 males; mean age of 44.5 and average time of the disease of 11.2 years. The most frequent etiology was post-surgical. Levels of serum calcium and creatinine increased between the first and last visits (p < 0.001 and p < 0.05, respectively); and serum levels of phosphate decreased during the same period (p < 0.001). Out of the 55 patients, 40 had USG, and 10 (25%) presented with kidney calcifications. There was no significant difference in the amount of calcium and vitamin D doses among patients with kidney calcifications and others. No correlation between serum and urinary levels of calcium and the presence of calcification was found. Urinary calcium excretion in 24h was significantly higher in patients with kidney calcification (3.3 mg/kg/d) than in those without calcification (1.8 mg/kg/d) (p < 0.05). Conclusions The reduction of hypocalcemia and hyperphosphatemia suggest an effectiveness of the treatment, and the increase in serum creatinine demonstrates an impairment of renal function during follow-up. Kidney calcifications were prevalent in this cohort, and higher urinary calcium excretion, even if still within the normal range, was associated with development of calcification. These findings suggest that lower rates of urinary calcium excretion should be aimed for in the management of hypoparathyroidism.

Histomorphometric changes following treatment for osteoporosis

demonstrated that mineral apposition rate (MAR) was unchanged, confirming that there is no inhibition of bone mineralization, despite the reduction in bone remodeling rate. Furthermore, alendronate had minimal effect on the parameters related to bone resorption such as osteoclast number and eroded surface. Bone microarchitecture, cancellous bone volume, and cortical thickness are preserved with antiresorptive treatments. After 3 years of treatment with risedronate, a paired biopsy study in postmenopausal women showed a decrease in bone remodeling associated with preservation of bone structure. The diminution of bone remodeling with risedronate is less than that which occurs with zoledronic acid and denosumab, which are considered to be more potent antiresorptive agents. In the FREEDOM trial of denosumab bone, biopsies were performed after 24 or 36 months of treatment [3]. They showed a significant reduction in eroded surface and osteoclast number with denosumab compared to placebo. In addition, dynamic parameters were reduced by denosumab treatment with the median bone formation rate being reduced by 97% in comparison to placebo. In fact, double tetracycline labeling in trabecular bone was observed in only 40% of the patients treated with denosumab, while it was present in 100% of the placebo group. However, it is important to note that, among patients on denosumab, those who had tetracycline labels and those without labels had similar circulating bone turnover marker levels. This finding suggests that lack of labels at the iliac crest does not necessarily mean absence of bone remodeling in other skeletal sites [3]. The STAND trial compared denosumab to alendronate and showed that indices of bone turnover were lower in patients treated with denosumab than with alendronate, confirming the more potent antiresorptive effect of denosumab seen with biochemical markers [3]. Furthermore, it is important to note that the effects of denosumab A significant body of information is available regarding the effects of osteoporosis drugs on bone histomorphometry [1, 2]. This is, in part, because regulatory agencies require biopsies to be performed to assess the safety and mechanism of action of new therapeutic agents. There are two classes of osteoporosis drugs: antiresorptive and anabolic. As revealed by bone histomorphometry, each class has a fundamentally different mechanism of action. Antiresorptive therapies, such as estrogen, calcitonin, raloxifene, bisphosphonates, and denosumab, decrease bone turnover, lowering both resorption, and formation [2]. There are several histomorphometric studies on the effect of hormone therapy (HT) in postmenopausal women, providing convincing evidence of its beneficial skeletal action in preserving bone volume and structure by decreasing bone turnover. The reduction in bone remodeling parameters after treatment with HT is more pronounced than that observed with raloxifene or calcitonin. Similarly, bone biopsy studies following treatment with bisphosphonates show a reduction in the rate of bone remodeling with a decrease in osteoid surface and in the tetracycline-based, dynamic parameters of bone turnover: mineralizing surface, bone formation rate and activation frequency. However, a study analyzing biopsies obtained after 2–3 years of alendronate treatment