Form Of Secondary Osteoporosis Research Articles

High prevalence of vertebral fractures associated with preoperative cortisol levels in patients with recent diagnosis of Cushing disease

Background/objective Morphometric vertebral fractures (VFs) and osteopathy are prevalent and clinically significant complications of Cushing disease (CD). However whether they represent an early occurrence in the natural progression of the disease is an ongoing debate. This study aimed to assess the prevalence and determinants of VFs in patients newly diagnosed with CD. Patients and methods This cross-sectional case–control study recruited 75 newly diagnosed CD patients and compared them with a control group of individuals without pituitary disorders or secondary forms of osteoporosis. Demographic, clinical and biochemical data were collected. The VFs were assessed using preoperative lateral chest radiography. Results We found a significantly higher prevalence of VFs in the CD group than in the control group (58.7% vs. 14.5%; P < 0.001). Among the CD patients with VFs, 27 (61.4%) showed moderate/severe VFs. The CD patients with VFs had significantly higher preoperative 8 am serum cortisol (8ASC) levels than those without VFs (P < 0.001). The preoperative 4 pm adrenocorticotropic hormone (ACTH) levels (P = 0.031), preoperative 0 am ACTH levels (P = 0.021) and systolic blood pressure were slightly higher in CD patients with VFs than in those without VFs (P = 0.028). A binary multiple logistic analysis showed that 8ASC was an independent predictor of VF risk (P = 0.003). The optimal cut-off value of the preoperative serum 8ASC level for predicting VFs was 22.18 ng/mL. Conclusions This is the first study reporting a high prevalence of radiologic VFs in recently diagnosed CD patients. VFs may represent an early manifestation of CD and may be related to cortisol levels. Therefore, VF assessment should be included in the workup during CD diagnosis.

A Novel RANKL-Targeted Furoquinoline Alkaloid Ameliorates Bone Loss in Ovariectomized Osteoporosis through Inhibiting the NF-κB Signal Pathway and Reducing Reactive Oxygen Species.

Dysregulation of osteoclast-osteoblast balance, resulting in abnormal bone remodeling, is responsible for postmenopausal osteoporosis (PMOP) or other secondary forms of osteoporosis. We demonstrated that dictamnine (DIC), a novel RANKL-targeted furoquinoline alkaloid, inhibits osteoclastogenesis by facilitating the activities of reactive oxygen species (ROS), NF-κB, and NFATc1 in vitro and prevents the development of OVX-induced osteoporosis mouse models in vivo. Methods. The docking mechanism of DIC and RANKL was initially identified by protein-ligand molecular docking. RNA sequencing was performed and analyzed to reveal the potential mechanism and signaling pathway of the antiosteoporosis effects of DIC. To verify the sequencing results, we examined the impact of DIC on RANKL-induced osteoclast differentiation, bone resorption, F-actin ring production, ROS generation, and NF-κB activation in osteoclasts in vitro. Moreover, a luciferase assay was performed to determine the binding and transcriptional activity of Nrf2 and NF-κB. The in vivo efficacy of DIC was assessed with an ovariectomy- (OVX-) induced osteoporosis model, which was analyzed using micro-CT and bone histomorphometry. Results. The molecular docking results indicated that DIC could bind particularly to RANKL. RNA-seq confirmed that DIC could regulate the osteoclast-related pathway. DIC suppressed osteoclastogenesis, bone resorption, F-actin belt formation, osteoclast-specific gene expression, and ROS activity by preventing NFATc1 expression and affecting NF-κB signaling pathways in vitro. The luciferase assay showed that DIC not only suppressed the activity of Nrf2 but also contributed to the combination of Nrf2 and NF-κB. Our in vivo study indicated that DIC protects against OVX-induced osteoporosis and preserves bone volume by inhibiting osteoclast activity and function. Conclusions. DIC can ameliorate osteoclast formation and OVX-induced osteoporosis and therefore is a potential therapeutic treatment for osteoporosis.

Melatonin Inhibits the Ferroptosis Pathway in Rat Bone Marrow Mesenchymal Stem Cells by Activating the PI3K/AKT/mTOR Signaling Axis to Attenuate Steroid-Induced Osteoporosis.

Steroid-induced osteoporosis (SIOP) is a form of secondary osteoporosis, but its specific mechanism remains unclear. Glucocorticoid (GC-)-induced death of osteoblasts and bone marrow mesenchymal stem cells (BMSCs) is an important factor in SIOP. Ferroptosis is an iron-dependent type of programmed cell death and can be induced by many factors. Herein, we aimed to explore whether GCs cause ferroptosis of BMSCs, identify pathways as possible therapeutic targets, and determine the underlying mechanisms of action. In this study, we used high-dose dexamethasone (DEX) to observe whether GCs induce ferroptosis of BMSCs. Additionally, we established a rat SIOP model and then assessed whether melatonin (MT) could inhibit the ferroptosis pathway to provide early protection against GC-induced SIOP and investigated the signaling pathways involved. In vitro experiments confirmed that DEX induces ferroptosis in BMSCs. MT significantly alleviates GC-induced ferroptosis of BMSCs. Pathway analysis showed that MT ameliorates ferroptosis by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) axis. MT upregulates the expression of PI3K, which is an important regulator of ferroptosis resistance. PI3K activators mimic the antiferroptotic effect of MT, but when the PI3K pathway is blocked, the effect of MT is weakened. Using in vivo experiments, we confirmed the in vitro results and observed that MT can obviously protect against SIOP induced by GC. Notably, even after the initiation of GC-induced ferroptosis, MT can confer protection against SIOP. Our research confirms that GC-induced ferroptosis is closely related to SIOP. MT can inhibit ferroptosis by activating the PI3K/AKT/mTOR signaling pathway, thereby inhibiting the occurrence of SIOP. Therefore, MT may be a novel agent for preventing and treating SIOP.

Secondary Osteoporosis and Metabolic Bone Diseases.

Fragility fracture is a worldwide problem and a main cause of disability and impaired quality of life. It is primarily caused by osteoporosis, characterized by impaired bone quantity and or quality. Proper diagnosis of osteoporosis is essential for prevention of fragility fractures. Osteoporosis can be primary in postmenopausal women because of estrogen deficiency. Secondary forms of osteoporosis are not uncommon in both men and women. Most systemic illnesses and organ dysfunction can lead to osteoporosis. The kidney plays a crucial role in maintaining physiological bone homeostasis by controlling minerals, electrolytes, acid-base, vitamin D and parathyroid function. Chronic kidney disease with its uremic milieu disturbs this balance, leading to renal osteodystrophy. Diabetes mellitus represents the most common secondary cause of osteoporosis. Thyroid and parathyroid disorders can dysregulate the osteoblast/osteoclast functions. Gastrointestinal disorders, malnutrition and malabsorption can result in mineral and vitamin D deficiencies and bone loss. Patients with chronic liver disease have a higher risk of fracture due to hepatic osteodystrophy. Proinflammatory cytokines in infectious, autoimmune, and hematological disorders can stimulate osteoclastogenesis, leading to osteoporosis. Moreover, drug-induced osteoporosis is not uncommon. In this review, we focus on causes, pathogenesis, and management of secondary osteoporosis.

High Prevalence of Vertebral Fractures Associated With Preoperative GH Levels in Patients With Recent Diagnosis of Acromegaly.

Osteopathy and morphometric vertebral fractures (VFs) are emerging complications in acromegaly. However, the prediction of VFs in this clinical setting is still a matter of uncertainty, and it is debated whether they are an early event in the natural history of the disease. We aimed to evaluate the prevalence and determinants of morphometric VFs in patients with recently diagnosed acromegaly. We enrolled 92 patients (43 men/49 women) on admission to the neurosurgery unit before transsphenoidal surgery, and compared them with control individuals without secondary forms of osteoporosis and pituitary disorders. We performed a VF assessment on preoperative chest x-ray images and collected biochemical, demographic, and clinical data. We detected a significantly higher prevalence of VFs (33.7%) in patients with acromegaly than in controls (P = .001). Among the patients with acromegaly and VFs, 12 (38.7%) showed multiple VFs, and 5 (16.1%) showed moderate/severe VFs. Patients with VFs had higher random serum growth hormone (GH) levels than those with no VFs (P = .03), but there was no difference in insulin-like growth factor-1 (IGF-1) (P = .07) and IGF-1/Upper Normal Limit ratio (P = .08). Free 3,5,3'-triiodothyronine was slightly lower in patients with acromegaly and VFs than in those without VFs (P = .05). In multiple logistic analysis, GH was independently associated with risk for VFs (P = .003). The preoperative serum GH cutoff value that predicted VFs was 12 ng/mL. For the first time, high prevalence of radiological VFs is reported in patients with recent diagnosis of acromegaly. Therefore, we can hypothesize that VFs are an early phenomenon of acromegaly and related to GH levels. VF assessment should be included in the workup at the diagnosis of acromegaly.

Prevalence of vertebral fractures and serum sclerostin levels in acromegaly.

An increased prevalence of vertebral fractures (VFs) has been reported in previous studies. The aim of this study was to evaluate the association between bone mineral density (BMD), bone turnover markers, serum sclerostin levels, and vertebral fractures (VFs) in acromegaly patients. We also evaluated the effects of gonadal status, disease activity, treatment modality, age, sex, and body mass index (BMI) on skeletal endpoints. Case-control study. Seventy acromegaly patients (M/F:36/34, mean age 45.5 ± 11.9 years) and 70 controls (M/F:31/39; mean age 45.66 ± 11.9 years) were included. VFs, BMD, calcium metabolism, markers of bone turnover, and sclerostin levels were evaluated. BMD was measured by dual-energy X-ray absorptiometry (Hologic QDR 4500). Conventional lateral radiography of the spine was performed and the Genant method was used for the assessment of fractures of T4-L5 vertebrae. The prevalence of vertebral fractures was higher in acromegalic patients as compared with the control group (72.9 vs. 20%; p < 0.001). Serum phosphate (P) levels (3.46 ± 0.59 mg/dl vs. 3.11 ± 0.44 mg/dl; p < 0.001) and b-cross laps (CTx) levels (0.47 µg/l, range 0.04-2.38 vs. 0.28 µg/l, range 0.11-0.80; p < 0.001) were significantly higher in acromegaly patients than control subjects. Serum sclerostin levels were similar between either acromegaly patients and control subjects or acromegaly patients with VF and without VF. In the means of treatment modality, VFs were more frequent in patients treated with adjuvant gamma knife radiosurgery (GKS) (p = 0.07). In the binary logistic regression analysis, the age of the acromegaly patients, the presence of hypogonadism, and GKS treatment were the factors significantly correlated with the occurrence of spinal fractures. The prevalence of VFs in patients with acromegaly is higher than in control subjects. Since advanced age, the presence of hypogonadism and GKS treatment were the factors predicting VFs in acromegaly; radiological evaluations should be considered as an emerging tool especially in those patients. Although markers of bone turnover elevated in acromegaly, they were not useful for the prediction of fractures. Serum sclerostin levels showed no discrepancy between the two groups and further studies are required for assessment of sclerostin role in this form of secondary osteoporosis.

Pharmacological management of osteoporosis in postmenopausal women: The current state of the art.

Osteoporosis is a common disease that increases fracture risk. Fragility fractures bring heavy consequences in terms of mortality and disability, with burdensome health and social costs. In subjects with clinical bone fragility, the first goal is to identify the secondary forms of osteoporosis, especially in young subjects, in males and in patients who recently experienced a fragility fracture. In addition, before considering any sort of treatment, it is fundamental to check for adequate calcium and vitamin D intake, since their deficiency is the most common reason for drug failure.In the last decade of the 20th century, several molecules have been developed and proved to be effective in achieving the true goal of any antiosteoporotic drug: fracture prevention.In this article, we considered the most commonly prescribed antiresorptive drugs (hormonal therapy, bisphosphonates, and denosumab), the anabolic agents (teriparatide), the dual-action drugs (romosozumab), and the drugs characterized by an unclear mechanism of action (strontium ranelate) to provide physicians with useful insights for their clinical practice. We discussed the main criteria for the appropriate choice selection and management of each treatment. Finally, we addressed the current controversies related to treatment discontinuation, sequential, and combination therapy.

Risk of vertebral fractures in hypoparathyroidism.

Parathyroid hormone (PTH) exerts both anabolic and catabolic actions on bone,depending on the duration and periodicity of exposure. Hypoparathyroidism is defined by inadequate production of PTH in the presence oflow serum calcium. In hypoparathyroidism it has been reported an increase in corticaland trabecular bone mass, but it is still unknown if these quantitative variations maybe accompanied by qualitative ones and increased bone strength. Despite the extensive data available on the effects of hypoparathyroidism on bone, itseffect on the hard end point in this area which is the risk of fractures still remainsunresolved and highly debated. As a matter of fact no previous review has focused onthis relevant clinical topic. This review will deal with the various aspects of bone metabolism (turn-over,density, quality) in hypoparathyroidism, focusing on the few data available on therisk of fracture and in particular of morphometric vertebral fractures, the emerging way to assess actual skeletal fragility particularly in secondary forms of osteoporosis.

P43. Percutaneous vertebroplasty for vertebral compression fracture in glucocorticosteroid-induced osteoporosis: a case-control study

BACKGROUND CONTEXT Glucocorticoids-induced osteoporosis (GIOP) is a common form of secondary osteoporosis that often precipitates osteoporotic vertebral compression fracture (VCF). Comparing to conservative therapeutic strategies for VCF, percutaneous vertebroplasty (PVP) could quickly relieve back pain and improve overall life quality. But recent studies demonstrate that the risk of refracture following PVP surgery is high among patients with GIOPVCF. Thus, it is vital that the outcomes of different treatments for GIOPVCF are clearly understood and the clinical guidelines for treating this disease are defined. We designed a prospective cohort study to compare differences of therapeutic effects and incidence of refractures between conservative treatment and PVP for GIOPVCF. PURPOSE To investigate the clinical characteristics of vertebral compression fracture (VCF) in glucocorticosteroid-induced osteoporosis (GIOP) and risk of vertebral refracture after percutaneous vertebroplasty (PVP) STUDY DESIGN/SETTING A retrospective cohort study. PATIENT SAMPLE A total of 570 cases who received PVP as treatments of VCF from January 2010 to December 2013 were retrospective reviewed. Forty-two cases were GIOP and 21 cases were followed up as GIOP group, other 528 cases were primary osteoporosis and 391 cases were followed up, 84 cases of them were selected based on age and gender as control group. OUTCOME MEASURES Primary Outcome Measure: Incidence of vertebral refracture; Secondary Outcome Measure: fracture location, ratio of single segment fracture and multiple segments fracture in two groups. METHODS Compared the fracture location, ratio of single segment fracture and multiple segments fracture in two groups. In final follow up, compared the reoperation rate for vertebral refractures by the Kaplan-Meier methodin two groups. RESULTS Follow-up period were 24.0±13.1 months in GIOP group and 25.8±14.4 months in control group (P>0.05). In GIOP group, there were 11 cases with one-segment fracture, 2 cases with two-segments fracture, 3 cases with three-segments fracture, 2 cases with four-segments fracture, 2 cases with five-segments fracture and 1 case with eight-segments fracture. In control group, there were 67 cases with one-segment fracture, 12 cases with two-segments fracture, 3 cases with three-segment fracture, 2 cases with four-segments fracture. The ratio of single segment fracture in GIOP group was significantly lower than that in control group (52.4% vs 79.8%, P=0.01. There were 50 fracture segments in GIOP group and 109 fracture segments in control group. The ratio of fracture segments located in thoracic segments (T1-T10, thoracolumbar segments (T11-L1) and lumbar segments (L2-L5) was 18%, 46% and 36% in GIOP group and 11.9%,58.7% and 29.4% in control group (P>0.05). The refracture rate in GIOP group was higher than that in control group (23.8% vs 6.0%. The survival rate is lower in GIOP group than that in control group (P CONCLUSIONS Predilection site of VCF was similar in GIOP and primary osteoporosis (thoracolumbar segments> thoracic segments > lumbar segments). The risk of multiple segments VCF was higher in GIOP than in primary osteoporosis. The risk of vertebral refractures after PVP was higher in GIOP than in primary osteoporosis. FDA DEVICE/DRUG STATUS Stryker PCD Mixer and Delivery System (Approved for this indication).

Pituitary Diseases and Bone.

Neuroendocrinology of bone is a new area of research based on the evidence that pituitary hormones may directly modulate bone remodeling and metabolism. Skeletal fragility associated with high risk of fractures is a common complication of several pituitary diseases such as hypopituitarism, Cushing disease, acromegaly, and hyperprolactinemia. As in other forms of secondary osteoporosis, pituitary diseases generally affect bone quality more than bone quantity, and fractures may occur even in the presence of normal or low-normal bone mineral density as measured by dual-energy X-ray absorptiometry, making difficult the prediction of fractures in these clinical settings. Treatment of pituitary hormone excess and deficiency generally improves skeletal health, although some patients remain at high risk of fractures, and treatment with bone-active drugs may become mandatory. The aim of this review is to discuss the physiological, pathophysiological, and clinical insights of bone involvement in pituitary diseases.

Synthesis, characterization, and cytocompatibility of potential cockle shell aragonite nanocrystals for osteoporosis therapy and hormonal delivery.

Calcium carbonate is a porous inorganic nanomaterial with huge potential in biomedical applications and controlled drug delivery. This study aimed at evaluating the physicochemical properties and in vitro efficacy and safety of cockle shell aragonite calcium carbonate nanocrystals (ANC) as a potential therapeutic and hormonal delivery vehicle for osteoporosis management. Free and human recombinant parathyroid hormone 1-34 (PTH 1-34)-loaded cockle shell aragonite calcium carbonate nanocrystals (PTH-ANC) were synthesized and evaluated using standard procedures. Transmission electron microscopy and field emission scanning electron microscopy results demonstrated highly homogenized spherical-shaped aragonite nanocrystals of 30±5 nm diameter. PTH-ANC had a zeta potential of −27.6±8.9 mV. The encapsulation efficiency of the formulation was found to be directly proportional to the concentrations of the drug fed. The X-ray diffraction patterns revealed strong crystallizations with no positional change of peaks before and after PTH-ANC synthesis. Fourier transform infrared spectroscopy demonstrated no detectable interactions between micron-sized aragonite and surfactant at molecular level. PTH-ANC formulation was stabilized at pH 7.5, enabling sustained slow release of PTH 1-34 for 168 h (1 week). A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cytocompatibility assay in Human Foetal Osteoblast Cell Line hFOB 1.19 showed that ANC can safely support osteoblast proliferation up to 48 h whereas PTH-ANC can safely support the proliferation at 72 h and beyond due to the sustained slow release of PTH 1-34. It was concluded that due to its biogenic nature, ANC is a cytocompatible antiosteoporotic agent. It doubles as a nanocarrier for the enhancement of efficacy and safety of the bone anabolic PTH 1-34. ANC is expected to reduce the cost, dosage, and dose frequency associated with the use of PTH 1-34 management of primary and secondary forms of osteoporosis.

Bone loss at the distal femur and proximal tibia in persons with spinal cord injury: imaging approaches, risk of fracture, and potential treatment options.

Persons with spinal cord injury (SCI) undergo immediate unloading of the skeleton and, as a result, have severe bone loss below the level of lesion associated with increased risk of long-bone fractures. The pattern of bone loss in individuals with SCI differs from other forms of secondary osteoporosis because the skeleton above the level of lesion remains unaffected, while marked bone loss occurs in the regions of neurological impairment. Striking demineralization of the trabecular epiphyses of the distal femur (supracondylar) and proximal tibia occurs, with the knee region being highly vulnerable to fracture because many accidents occur while sitting in a wheelchair, making the knee region the first point of contact to any applied force. To quantify bone mineral density (BMD) at the knee, dual energy x-ray absorptiometry (DXA) and/or computed tomography (CT) bone densitometry are routinely employed in the clinical and research settings. A detailed review of imaging methods to acquire and quantify BMD at the distal femur and proximal tibia has not been performed to date but, if available, would serve as a reference for clinicians and researchers. This article will discuss the risk of fracture at the knee in persons with SCI, imaging methods to acquire and quantify BMD at the distal femur and proximal tibia, and treatment options available for prophylaxis against or reversal of osteoporosis in individuals with SCI.

The Radiology of Vertebral Fractures in Childhood Osteoporosis Related to Glucocorticoid Administration

A number of unusual conditions cause decreased bone mass and density in children and these may be associated with low-trauma fractures. However, a series of reports have more recently identified that children with chronic disease sustain vertebral fractures (VFs) much more often than had been suspected. The common denominator involved is glucocorticoid (GC) administration, although other factors such as disease activity come into play. This review will focus on the imaging findings in this form of secondary osteoporosis. Spinal fractures in children have been found to correlate with back pain. At the same time, up to 2/3 of children with VFs in the GC-treated setting are asymptomatic, underscoring the importance of routine surveillance in at-risk children. Other predictors of prevalent and incident VFs include GC exposure (average daily and cumulative dose), declines in lumbar spine bone mineral density Z-scores and increases in body mass index Z-scores, as well as increases in disease activity scores. The imaging diagnosis of osteoporotic VFs in children is made differently from that in adults because immature vertebral bodies continue to ossify during growth. Thus, it is not possible to assess the vertebral end plates or periphery until late, as enchondral ossification extends centripetally within the centrum. Diagnosis, therefore, is much more dependent upon changes in shape than on loss of structural integrity, which may have a more prominent diagnostic role in adults. However, children have a unique ability to model (a growth-dependent process) and thereby reshape previously fractured vertebral bodies. If the underlying disease is successfully treated and the child has sufficient residual growth potential, this means that, on one hand, treatment of the bone disease may be of more limited duration, and, as a last recourse, the diagnosis may be apparent retrospectively.

Parathyroid hormone pulsatility: physiological and clinical aspects.

Parathyroid hormone (PTH) secretion is characterized by an ultradian rhythm with tonic and pulsatile components. In healthy subjects, the majority of PTH is secreted in tonic fashion, whereas approximately 30% is secreted in low-amplitude and high-frequency bursts occurring every 10–20 min, superimposed on tonic secretion. Changes in the ultradian PTH secretion were shown to occur in patients with primary and secondary osteoporosis, with skeletal effects depending on the reciprocal modifications of pulsatile and tonic components. Indeed, pathophysiology of spontaneous PTH secretion remains an area potentially suitable to be explored, particularly in those conditions such as secondary forms of osteoporosis, in which conventional biochemical and densitometric parameters may not always give reliable diagnostic and therapeutic indications. This review will highlight the literature data supporting the hypothesis that changes of ultradian PTH secretion may be correlated with skeletal fragility in primary and secondary osteoporosis.

Role of bone mineral density in predicting morphometric vertebral fractures in patients with HIV infection.

This study investigated the bone of HIV patients both in terms of quantity and quality. It was found that HIV-infected patients did fracture independently of the degree of bone demineralization as in other forms of secondary osteoporosis. We aimed to determine the prevalence of vertebral fractures (VFs) in HIV patients who were screened by bone mineral density (BMD) and to explore possible factors associated with VFs. This is a cross-sectional study that included HIV-infected patients recruited in the Clinic of Infectious and Tropical Diseases and that underwent BMD measurement by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and hip (Lunar Prodigy, GE Healthcare). For the assessment of VFs, anteroposterior and lateral X-ray examinations of the thoracic and lumbar spines were performed and were centrally digitized. Logistic regression models were used in the statistical analysis of factors associated with VFs. One hundred thirty-one consecutive patients with HIV infection (93 M, 38 F, median age 51years; range, 36-75) underwent BMD measurement: 25.2% of patients showed normal BMD, while 45% were osteopenic and 29.7% osteoporotic. Prevalence of low BMD (osteopenia and osteoporosis) was higher in females as compared to males (90 vs 69%) with no significant correlation with age and body mass index. VFs occurred more frequently in patients with low BMD as compared to patients with normal BMD (88.5 vs. 11.4%; p < 0.001) without any significant difference between osteopenia and osteoporosis (43 vs. 46%; p = 0.073). VFs were significantly associated with older age and previous AIDS events. These results suggest a BMD <-1 threshold to identify patients at risk of skeletal fragility and, therefore, good candidates for morphometric evaluation of spine X-ray in line with other forms of secondary osteoporosis with impaired bone quality.

Could zinc supplementation improve bone status in growth hormone (GH) deficient children?

Reduced bone mineral density (BMD) and increased fracture rate have been reported in subjects with either childhood or adult onset growth hormone (GH) deficiency (GHD), more severe in childhood onset GHD [1, 2]. A longer gap in GH replacement in adults with childhood onset GHD is associated with a lower bone mineralization and GH replacement has been suggested having a critical role in transition to adulthood to optimize bone accrual [3]. Furthermore, also a delay in starting GH replacement in GHD adults may be associated with a persistent increase in vertebral fracture risk [4]. However, many criticisms have been raised on these assumptions. Limitations of current bone imaging techniques have caused many artefacts about BMD and bone structure. Using appropriate size corrections, BMD is normal in children and adults with isolated GHD in several studies and the anabolic changes in muscle mass and strength may contribute to the observed bone changes [for critical reviews see 5, 6]. Briefly, many historical studies used T-scores in GHD children, comparing children’s BMD with adult reference data. On the other hand, when age—and sex—Z scores have been introduced for the pediatric population, height remained a confounding factor and being tall or short for age leads to a false negative or a false positive result for BMD Z-score, respectively. Since 2008, official positions of the International Society for Clinical Densitometry strongly recommend size correction for DXA measurements in the pediatric age [7]; however, no consensus exists how to correct measurements. To date, the most real effect of GHD on bone seems to be a reduction in bone volume ratio and trabecular thickness in both animal and human studies [5, 6]. Moreover, we must not forget that GH replacement causes biphasic effects on the bone remodeling with early stimulation of bone resorption followed by a sustained increase in bone formation [8]: some controversial results of published literature could be due to the time from the start of the therapy. On the other hand, it is unclear whether changes in BMD may really predict the fracture risk in patients with GHD, as well as other forms of secondary osteoporosis, being other markers of bone quality still searched. The first point in favor of the paper by Ekbote et al. [9] in this issue of Endocrine is that the Authors performed size correction for DXA bone mineral content (BMC) and bone area (BA) measurements using height. They showed that in Indian prepubertal children with isolated GHD, height adjusted BMC and BA significantly increased of 48 and 40 %, respectively, after 1 year of GH treatment. These changes were associated with an increase in height adjusted lean body mass and a decrease in height adjusted body fat. Many previous studies in childhood onset GHD, in particular in Italian and Dutch cohorts, reported an increase in BMC in the range of 2–10 %, significantly lower than that observed in the present study [5, 6]. However, it has to be emphasized that the majority of other studies did not perform any size correction. Furthermore, the population investigated in this study [9] presented a very low BMC at baseline and this aspect could have influenced the results. However, we can first speculate that when BMC is clearly reduced in GHD patients, a treatment with rhGH works in improving bone health. Bone metabolism is complex. Many factors tightly regulate BMC and bone accrual, mainly, among others, F. Prodam SCDU of Pediatrics, Department of Health Sciences, Universita del Piemonte Orientale ‘‘A. Avogadro’’, Novara, Italy

New understanding and treatments for osteoporosis

To summarize promising areas of investigation in osteoporosis and to stimulate further research in this area, as discussed in a recent international conference. Over the recent years, there has been an improvement in the knowledge of molecular pathways involved in bone formation and resorption with the development of new drugs to treat osteoporosis. Intact parathyroid hormone, teriparatide, and anti-sclerostin monoclonal antibody are anabolic drugs, whereas denosumab and odanacatib are anti-resorptive drugs with more reversible effects as compared to bisphosphonates. Anabolic and anti-resorptive agents have different effects on bone, and research in this area includes the efficacy of combination and sequential therapies with them. New insights in the molecular pathways of bone remodeling have clarified the mechanisms responsible for skeletal fragility in several forms of secondary osteoporosis, such as that occurring in type 2 diabetes, following drug exposure and systemic inflammatory diseases. Future research is needed to address the efficacy of anti-osteoporotic drugs in these more recently recognized conditions of skeletal fragility. Osteoporosis continues to be an important field of biomedical research.

New tools for detecting occult monoclonal gammopathy, a cause of secondary osteoporosis

Most patients with multiple myeloma or other monoclonal gammopathies present with anemia, hypercalcemia, or renal insufficiency. However, osteoporosis may be the first sign. Measuring the concentration and ratio of free light chains in the serum can help detect monoclonal gammopathy and help to differentiate myeloma-related bone loss from other secondary forms of osteoporosis.

Approach to the patient with secondary osteoporosis

Secondary osteoporosis is characterized by low bone mass with microarchitectural alterations in bone leading to fragility fractures in the presence of an underlying disease or medication. Scenarios that are highly suspicious for secondary osteoporosis include fragility fractures in younger men or premenopausal women, very low bone mineral density (BMD) values, and fractures despite anti-osteoporotic therapy. An open-minded approach with a detailed history and physical examination combined with first-line laboratory tests are aimed at identifying clinical risk factors for fractures, osteoporosis-inducing drugs, and underlying endocrine, gastrointestinal, hematologic, or rheumatic diseases, which then need to be confirmed by specific and/or more invasive tests. BMD should be assessed with bone densitometry at the hip and spine. Lateral X-rays of the thoracic and lumbar spine should be performed to identify or exclude prevalent vertebral fractures which may be clinically silent. Management of secondary osteoporosis includes treatment of the underlying disease, modification of medications known to affect the skeleton, and specific anti-osteoporotic therapy. Calcium and vitamin D supplementation should be initiated with doses that result in normocalcemia and serum 25-hydroxyvitamin D concentrations of at least 30 ng/ml. Oral and i.v. bisphosphonates are effective and safe drugs for most forms of secondary osteoporosis. Severe osteoporosis may require the use of teriparatide.

Laboratory diagnostics in the prevention, differential diagnosis, and monitoring of osteoporosis1

Abstract The World Health Organization ranks osteoporosis as one of the economic most significant diseases of the 21st century. Apart from anamnesis, physical examination and imaging techniques, laboratory tests are important tools in the diagnosis and monitoring of osteoporosis. Basic laboratory tests can be distinguished from advanced laboratory tests. The basic laboratory tests are used to differentiate between the primary and secondary form of osteoporosis. Further laboratory tests can clarify the causation of secondary forms of osteoporosis. Biochemical markers of bone turnover are particularly used for monitoring the therapy and the course of osteoporosis.