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Primary osteoporosis is rare in children and adolescents and its optimal pharmacological management is uncertain. Bisphosphonates are commonly used while denosumab has only been administered to a few children with osteogenesis imperfecta. We studied a treatment-naïve 13.5-year-old boy with severe osteoporosis and multiple vertebral deformities who presented with back pain and difficulty in walking. Causes of secondary osteoporosis were excluded and there were no abnormalities in genes known to cause bone fragility. He was treated with denosumab 60 mg subcutaneously every 3 months for 30 months, and he was pain-free within 6 weeks after the first injection. Lumbar spine BMD and femoral neck BMD increased with treatment by 65.6% and 25.3%, respectively, and deformed vertebrae regained their normal shape; linear growth was not impaired. During the second year of treatment, transient hypercalcemia (maximum 3.09 mmol/l) before the denosumab injection was observed. In conclusion, denosumab was highly effective in this case of primary pediatric osteoporosis, with remarkable clinical and radiological response. Transient hypercalcemia was probably due to amplification of the effect of growth spurt and puberty on bone remodeling by the transient, short-term discontinuation of the drug. Furthermore, our data suggest that mobilization of calcium from treatment-induced sclerotic transverse lines in bone metaphyses may contribute to the development of hypercalcemia. [ABSTRACT FROM AUTHOR]

Summary: A Greek-specific cost-effectiveness analysis determined the FRAX-based intervention thresholds. Assuming a willingness to pay of 30,000 €, osteoporosis treatment is cost-effective in subjects under the age of 75 with 10-year probabilities for hip and major osteoporotic fractures of 2.5 and 10 %, respectively, while for older patients, the same thresholds are raised to 5 and 15 %. Introduction: The purpose of this study was to determine the FRAX calculated fracture probabilities at which therapeutic intervention can be considered as cost-effective in the Greek setting. Methods: A Markov cohort model was populated with Greek data, and quality-adjusted life years (QALYs) were used to calculate the cost-effective thresholds for an annual medication cost of 733.7 € by gender and age. Average FRAX-based 10-year probabilities for both major osteoporotic and hip fractures were multiplied by the model-derived relative risk at which a cost of 30,000 € for each QALY gained was observed for treatment versus to no intervention. Results: A biphasic intervention threshold model is supported by our findings. Osteoporosis treatment becomes cost-effective when absolute 10-year probabilities for hip and major osteoporotic fractures reach 2.5 and 10 %, respectively, among both men and women under the age of 75. For older subjects, the proposed intervention thresholds are raised to 5 and 15 % 10-year probability for hip and major osteoporotic fractures, respectively. Conclusions: Cost-effective osteoporosis treatment may be facilitated in Greece if FRAX algorithm is used to identify subjects with 10-year probabilities for hip and major osteoporotic fractures of 2.5 and 10 %, under the age of 75, while for older patients, the relevant thresholds are 5 and 15 %, respectively. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The specific pharmacological properties of bisphosphonates have raised concerns about their long-term effects on skeletal fragility that may be related to the total dose of bisphosphonate given. However, the effect of different doses on the incidence of osteoporotic fractures has not been adequately studied. Methods: In this retrospective analysis, we investigated the effect of different doses of intravenous pamidronate given at 3-monthly intervals on the incidence of fractures in 92 women with severe postmenopausal osteoporosis. Results: The risk of sustaining a new vertebral fracture on treatment was significantly increased by 32% for every prevalent vertebral fracture (OR: 1.32, CI: 1.05, 1.66; p =0.02). Patients with nonvertebral fractures received a significantly lower dose of pamidronate and their risk for these fractures increased by 25% for every prevalent vertebral fracture at baseline (OR: 1.25, CI: 1.01, 1.53; p =0.03). Patients who had received oral bisphosphonate before intravenous pamidronate had a significantly higher incidence of nonvertebral fractures which, however, did not hold true after adjustment for baseline BMD and prevalent fractures. Conclusions: In patients with established osteoporosis bone fragility during treatment with intravenous pamidronate is mainly determined by the severity of the disease, assessed by the presence and numbers of prevalent fractures, rather than the dose of the bisphosphonate or the rate of bone turnover. [Copyright &y& Elsevier]

Background: Langerhans-cell histiocytosis (LCH) is a rare disease with features of chronic inflammation and it may also induce hypopituitarism, conditions associated with an increased risk of cardiovascular diseases. [ABSTRACT FROM PUBLISHER]

Langerhans cell histiocytosis (LCH) is a rare, systemic disease caused by monoclonal expansion of dendritic cells that shows a particular predilection for the hypothalamic–pituitary system (HPS). We studied the function (anterior and posterior pituitary hormonal secretion) and morphology using magnetic resonance imaging (MRI) of the HPS in 17 adult patients (seven males, median age 35 years, range 18–59 years) with multisystem LCH. We also evaluated the evolution of structural HPS abnormalities in relation to pituitary function and response to treatment in 12 of these patients during a median follow-up period of 3.75 years (range 1.5–10 years). Of the 17 patients, 14 (82%) had abnormal HPS imaging, and 12 (70%) had more than one area involved. Lack of the bright spot of the posterior pituitary lobe was typically found in all patients with the diagnosis of diabetes insipidus (DI). Eight patients (47%) had infundibular enlargement, six (35%) pituitary infiltration, four (24%) partially or completely empty sella, three (18%) hypothalamic involvement, and two (12%) infundibular atrophy. DI was found in 16 patients (94%) and anterior pituitary hormonal deficiency (APHD) in 10 patients (59%); two patients had single (12%) and 8 (47%) multiple APHD. During the follow-up period there was improvement of the initially demonstrated HPS pathology in seven (47%) patients, and five (33%) of them had received at least one form of treatment. APHD and DI persisted in all patients except in one in whom established gonadotrophin deficiency recovered. In summary, DI and APHD are very common in patients with multisystem LCH and are almost always associated with abnormal HPS imaging. [ABSTRACT FROM AUTHOR]

Summary: Antiresorptive medications do not negatively affect fracture healing in humans. Teriparatide may decrease time to fracture healing. Romosozumab has not shown a beneficial effect on human fracture healing. Background: Fracture healing is a complex process. Uncertainty exists over the influence of osteoporosis and the medications used to treat it on fracture healing. Methods: Narrative review authored by the members of the Fracture Working Group of the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF), on behalf of the IOF and the Société Internationale de Chirurgie Orthopédique et de Traumatologie (SICOT). Results: Fracture healing is a multistep process. Most fractures heal through a combination of intramembranous and endochondral ossification. Radiographic imaging is important for evaluating fracture healing and for detecting delayed or non-union. The presence of callus formation, bridging trabeculae, and a decrease in the size of the fracture line over time are indicative of healing. Imaging must be combined with clinical parameters and patient-reported outcomes. Animal data support a negative effect of osteoporosis on fracture healing; however, clinical data do not appear to corroborate with this. Evidence does not support a delay in the initiation of antiresorptive therapy following acute fragility fractures. There is no reason for suspension of osteoporosis medication at the time of fracture if the person is already on treatment. Teriparatide treatment may shorten fracture healing time at certain sites such as distal radius; however, it does not prevent non-union or influence union rate. The positive effect on fracture healing that romosozumab has demonstrated in animals has not been observed in humans. Conclusion: Overall, there appears to be no deleterious effect of osteoporosis medications on fracture healing. The benefit of treating osteoporosis and the urgent necessity to mitigate imminent refracture risk after a fracture should be given prime consideration. It is imperative that new radiological and biological markers of fracture healing be identified. It is also important to synthesize clinical and basic science methodologies to assess fracture healing, so that a convergence of the two frameworks can be achieved. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Severe spontaneous vertebral fractures after denosumab discontinuation: three case reports" by B. Aubry-Rozier and colleagues in the 2015 issue.

Summary: In vitro data suggest that myokine irisin may affect bone metabolism by promoting osteoblast differentiation while inhibiting osteoclast differentiation. In this study, circulating irisin levels were associated with previous osteoporotic fractures but not with bone mass and were not affected by denosumab or teriparatide treatment for 3 months. Introduction: This study aimed to evaluate predictors of circulating irisin in postmenopausal women with low bone mass and to assess a potential effect of denosumab or teriparatide treatment for 3 months. Methods: Serum samples for irisin measurement were obtained from (a) postmenopausal women with low bone mass (lumbar spinal [LS] or femoral neck [FN] bone mineral density [BMD] T-score ≤−2.0) and their age-matched controls at baseline and 3 months after denosumab (Dmab) injection (Dmab group, n = 50; Dmab control group, n = 25) and (b) women with more severe disease (LS or FN BMD T-score ≤−2.8) and their age-matched controls at the above-mentioned time points after teriparatide (TPTD) initiation (TPTD group, n = 25; TPTD control group, n = 25). Results: At baseline, irisin levels were inversely correlated with age (partial coefficient ( r) = −0.24; p = 0.009), parathyroid hormone (PTH) ( r = −0.30; p = 0.001), and creatinine ( r = −0.23; p = 0.016) in univariate analysis, and were lower in women with ( n = 26; 41.6 ± 2.7 ng/dL) than without previous osteoporotic fracture(s) ( n = 99; 51.0 ± 1.6 ng/dL; p = 0.007). In multiple linear regression, previous osteoporotic fracture(s) and PTH were independently negatively associated with irisin [ p = 0.04, CI −16.1 to −0.4 and p = 0.002, CI −0.3 to −0.07, respectively], but only the association with PTH remained after controlling for creatinine levels. Serum irisin levels were not different between women with or without low bone mass and were not affected by either Dmab or TPTD treatment for 3 months. Conclusions: Circulating irisin levels were associated with previous osteoporotic fracture(s); whether this association is independent or is due to confounding by lower muscle mass, potentially reflected by lower creatinine levels, remains to be fully clarified. [ABSTRACT FROM AUTHOR]

Periostin is a secreted extracellular matrix protein preferentially expressed in bone by osteocytes and periosteal osteoblasts. Reduced periostin expression may affect osteoblast differentiation and collagen type I synthesis and predispose to osteoporosis and increased fracture risk. We aimed to evaluate circulating periostin levels in postmenopausal women with low bone mass, their possible correlations with clinical and laboratory parameters, as well as the 3-month effect of zoledronic acid. Serum samples for periostin, 25-hydroxyvitamin D, parathyroid hormone (PTH), C-terminal telopeptide of type I collagen (CTx), and total alkaline phosphatase (tALP) were obtained from 46 postmenopausal women with low bone mass at baseline and 3 months after zoledronic acid infusion and from 30 agematched, postmenopausal controls with normal bone mass at baseline. There was no difference in periostin levels between women with normal and low bone mass (250 ± 15 vs. 272 ± 14 ng/ml, respectively; p = 0.279). Periostin remained essentially unchanged after zoledronic acid infusion (262 ± 18 ng/ml; p = 0.130). Serum periostin levels at baseline were not affected by previous bisphosphonate treatment, and were correlated only to tALP (rs = 0.351; p = 0.018). In multiple linear regression analysis, tALP (B = 3.17; 95 % CI = 0.59-5.79; p = 0.018) was associated with serum periostin levels at baseline, independently from previous anti-osteoporotic treatment, age, body mass index, and 25-hydroxyvitamin D. In conclusion, serum periostin levels do not differ between postmenopausal women with normal and low bone mass and are not affected by zoledronic acid treatment. Women with higher tALP have independently higher periostin levels. [ABSTRACT FROM AUTHOR]

Summary: Activin-A is expressed in bone and seems to regulate osteoclastogenesis. In this study, serum activin-A was increased in postmenopausal women with low bone mass and was positively correlated to age and negatively to lumbar spinal bone mineral density (BMD). Serum activin-A levels did not change 3 months after zoledronic acid infusion. Introduction: The aims of the study were to evaluate prospectively the circulating activin-A levels in postmenopausal women with low bone mass and explore possible correlations with clinical and laboratory data, as well as the 3-month effect of zoledronic acid infusion. Methods: Postmenopausal women with low bone mass assigned to receive zoledronic acid infusion (Patients, n = 47) and age-matched, postmenopausal women with normal bone mass (Controls, n = 27) were recruited on an outpatient basis. Main outcome measurement was serum activin-A levels. Results: Serum activin-A was higher in patients at baseline compared to controls ( p < 0.001) and activin-A in the serum of patients and controls was positively correlated with age (Spearman's coefficient of correlation [rs] = 0.325; p = 0.005) and negatively with lumbar spinal (LS) BMD (rs = −0.425; p < 0.001). In multiple linear regression analysis, only age (B = 8.93; 95 % CI = 4.39-13.46; p < 0.001) was associated with serum activin-A levels at baseline, independent from group (patients or controls), previous anti-osteoporotic treatment, LS BMD and follicle-stimulating hormone. Circulating activin-A levels were not affected 3 months after zoledronic acid infusion. Conclusions: Serum activin-A is increased in postmenopausal women with low bone mass compared with postmenopausal women with normal bone mass and is positively correlated to age and negatively to LS BMD. [ABSTRACT FROM AUTHOR]

Summary: Persistence with and adherence to osteoporosis therapy are critical for fracture reduction. This non-interventional study is evaluating medication-taking behavior of women with postmenopausal osteoporosis (PMO) receiving denosumab in Germany, Austria, Greece, and Belgium. Patients were representative of the PMO population and highly persistent with and adherent to denosumab at 12 months. Introduction: Persistence with and adherence to osteoporosis therapy are important for optimal treatment efficacy, namely fracture reduction. This ongoing, non-interventional study will evaluate medication-taking behavior of women with postmenopausal osteoporosis (PMO) receiving denosumab in routine practice in four European countries. Methods: The study enrolled women who had been prescribed subcutaneous denosumab (60 mg every 6 months) in accordance with prescribing information and local guidelines. Persistence was defined as receiving the subsequent injection within 6 months + 8 weeks of the previous injection. Adherence was defined as receiving two consecutive injections within 6 months ± 4 weeks of each other. Medication coverage ratio (MCR) was calculated using the time a patient was covered with denosumab, as assessed from prescription records. Treatment was assigned prior to and independently of enrollment; outcomes are recorded during routine practice. Results: These planned 12-month interim analyses included data from 1500 patients from 141 sites. Mean age was 66.4-72.4 years, mean baseline total hip T-scores ranged from −2.0 to −2.1 and femoral neck T-scores from −2.2 to −2.6, and 30.7-62.1 % of patients had prior osteoporotic fracture. Persistence was 87.0-95.3 %, adherence 82.7-89.3 %, and MCR 91.3-95.4 %. In a univariate analysis, increased age, decreased mobility, and increased distance to the clinic were associated with significantly decreased persistence; parental history of hip fracture was associated with significantly increased persistence. Conclusions: These data extend the real-world evidence regarding persistence with and adherence to denosumab, both of which are critical for favorable clinical outcomes, including fracture risk reduction. [ABSTRACT FROM AUTHOR]

Summary: Denosumab and zoledronic acid are potent antiresorptives. In this study in patients pre-treated with zoledronic acid, denosumab achieved similar increases with zoledronic acid in lumbar spine BMD despite the more prominent reduction of bone turnover markers. Denosumab reversibly reduced endogenous RANKL. Introduction: We aimed to compare yearly changes in lumbar spine (LS) bone mineral density (BMD), bone turnover markers, free soluble receptor activator of nuclear factor kappaB ligand (sRANKL) and sclerostin levels between denosumab and zoledronic acid. Methods: Postmenopausal women with low bone mass previously treated with zoledronic acid for 1 year were assigned to denosumab injection ( n = 32) or zoledronic acid infusion ( n = 26). Procollagen type 1 N-terminal propeptide (P1NP), C-terminal cross-linking telopeptide of type 1 collagen (CTx), sRANKL, and sclerostin levels were measured in serum samples obtained at baseline and 3, 6, and 12 months after denosumab injection or zoledronic acid infusion. LS BMD was measured at baseline and 12 months. Results: The mean LS increase was 4.5 and 4.4 % with denosumab and zoledronic acid, respectively ( p = 0.560). Denosumab caused a larger decrease in CTx at 3 months ( p < 0.001) and P1NP at 3 ( p < 0.001), 6 ( p = 0.021), and 12 months ( p = 0.042). Denosumab significantly decreased sRANKL by 87.4 % at 3 months ( p < 0.001). Sclerostin levels were not changed with either intervention ( p = 0.162 and p = 0.214, respectively). Conclusions: In patients previously treated with zoledronic acid, denosumab reduces bone turnover more than zoledronic acid, but the increases in LS BMD are comparable. Furthermore, denosumab administration results in reversible inhibition of the metabolically significant endogenous free soluble RANKL levels. Serum sclerostin is not affected by either agent. [ABSTRACT FROM AUTHOR]

Summary: The incidence of hip fractures doubled in Greece from 1977 to 2007 among people aged 50 and over. A mild decrease was observed after 2002, although the future trend cannot be safely anticipated at the moment. Half of all hip fractures in 2007 were derived from the age group of 80 and over. Introduction: The purpose of this study was to determine the incidence of hip fractures during a 30-year period in Greece among people aged 50 and over and to document possible alterations in secular trends. Methods: We studied hip fractures during 2007 and compared them with those of previous years starting from 1977 with an in-between 5-year interval (1977, 1982, 1987, 1992, 1997, 2002). Age- and sex-specific incidence was calculated, and secular trends were recorded. The relative risk of hip fracture in every age group was estimated according to the corresponding incidence of 1977. Results: The adjusted incidence of hip fractures increased approximately 100 % throughout the study; it progressively increased from 1977 to 2002 and exhibited a mild significant decrease thereafter. The relative risk of hip fractures among subjects aged 60-69 in 2007 has declined compared with 1977 [0.85, 95 % confidence intervals (CI) 0.79-0.92, p < 0.0005]. Among people aged 70-79, an increased relative fracture risk (1.53, 95 % CI 1.45-1.61, p < 0.0005) was estimated in 2007 compared with 1977. People ≥80 years old were responsible for half of the hip fractures in 2007 but only for the 22.5 % of fractures in 1977. The relative fracture risk in people aged ≥80 was 2.81 times higher (95 % CI 2.64-2.98, p < 0.0005) in 2007 than in 1977. Conclusions: The incidence of hip fractures doubled during the last 30 years among people aged ≥50 years, although a mild decrease was observed in almost all age groups after 2002. The most affected group is 80 and over. [ABSTRACT FROM AUTHOR]