The great challenge: bone fragility and environment.

Osteoporosis is a worldwide common disease characterised by reduced bone mass and increased risk of fractures.Many genetic variants are associated with the disease, but they account for only a small percentage of variance in individual bone mineral density and fragility fracture risk. Only recently have researchers recognised the role of a broad variety of environmental factors in the pathogenesis of osteoporosis, which has led to a further step: how genetic and environmental factors can interact, which is the next frontier in research on bone fragility.

Evaluating adherence, tolerability and safety of oral calcium citrate in elderly osteopenic subjects: a real-life non-interventional, prospective, multicenter study.

BACKGROUND: Osteoporosis is a common concern in the elderly that leads to fragile bones. Calcium supplementation plays a crucial role in improving bone health, reducing fracture risk, and supporting overall skeletal strength in this vulnerable population. However, there is conflicting evidence on the safety of calcium supplements in elderly individuals. AIM: The aim of this study was to evaluate the adherence, safety and tolerability of calcium citrate supplementation in elderly osteopenic subjects. METHODS: In this non-interventional, prospective, multicenter study, subjects received daily 500 mg calcium citrate supplementation for up to one year. Adherence was calculated based on compliance and persistence. Safety was assessed through adverse reactions (ARs), deaths, and clinical laboratory evaluations. RESULTS: A total of 268 Caucasian subjects (91.4% female, mean age 70 ± 4.5 years) participated in the study. Mean adherence to treatment was 76.6 ± 29.5% and half of subjects had an adherence of 91% and ~ 33% of participants achieved complete (100%) adherence. ARs were reported by nine (3.9%) subjects, primarily gastrointestinal disorders, with no serious ARs. The frequency of all adverse events (including ARs) was significantly higher in subjects with adherence of < 80% (41.6%; 32/77) vs. those with adherence ≥ 80% (11%; 16/145, p < 0.0001). Both systolic and diastolic blood pressure decreased from baseline to follow-up visit (change of -2.8 ± 13.9 mmHg, p = 0.0102 and -2.1 ± 10.4 mmHg, p = 0.0116, respectively). CONCLUSION: This study demonstrated favorable adherence to calcium citrate supplementation in elderly osteopenic subjects. The occurrence of ARs, though generally mild, were associated with lower adherence to calcium supplementation.

LRP5 high bone mass (Worth-type autosomal dominant endosteal hyperostosis): case report and historical review of the literature.

PURPOSE: LRP5 high bone mass (HBM) is an autosomal dominant endosteal hyperostosis caused by mutations of the low-density lipoprotein receptor-related protein 5 (LRP5) gene. Alternative names included "autosomal dominant osteosclerosis" and "Worth disease." The aim of the paper is to provide an historical overview of a disorder whose literature is complicated and confusing due to the past use of several denominations and lack of reviews. METHODS: We collected case reports of HBM with evidence of autosomal dominant transmission preceding the identification of the LRP5 mutations in 2002 (Worth-type endosteal hyperostosis) and cases of LRP5 HBM confirmed by genetic analysis since 2002. The prevalence of relevant clinical and laboratory findings was estimated. We described an affected woman with neurological manifestations. RESULTS: A 44-year-old Caucasian woman with torus palatinus complained of headache, hypo-/anosmia, and complete mixed deafness. Dual-energy X-ray absorptiometry (DEXA) scan revealed elevated bone mass. The A242T mutation of the LRP5 gene was detected. Including the present case, 155 patients have been reported to date. Neurological involvement and increased serum alkaline phosphatase (ALP) were present in 19.4% and 3.7% of cases, respectively. Facial changes and torus palatinus were observed in 61% and 41% of cases, respectively. CONCLUSIONS: We present the only historical review on Worth-type endosteal hyperostosis, now known as LRP5 HBM. Neurological manifestations, previously considered absent in the disease, affect 19.4% of the patients. Genetic analysis and appropriate denomination of LRP5 HBM are fundamental for diagnosis and to mitigate the confusion that has long characterized this disease.

Osteoporosis and gut microbiota, radiofrequency echographic multispectrometry and machine learning: one year in review 2023.

Osteoporosis is a prevalent bone disease with a relevant burden of mortality and comorbidity, especially due to fragility fractures occurring as a result of reduced bone mineral density. In this review we provide a critical digest of the most recent literature regarding the relationship between gut microbiota and osteoporosis, and discuss the role of radiofrequency echographic multi-spectrometry (REMS) and machine learning in the diagnostic work-up and prevention of osteoporosis.

Persistence and recurrence in tumor-induced osteomalacia: A systematic review of the literature and results from a national survey/case series.

PURPOSE: Tumor induced osteomalacia (TIO) is a rare disease of mineral metabolism, whose clinical picture is dominated by hypophosphatemia usually due to an excess of circulating FGF23 produced by small mesenchymal tumors. Data on the real prevalence of the disease are lacking, with the knowledge of the disease mainly relying on case reports and small case series. No estimate is available on the prevalence of uncured TIO. METHODS: National multi-center, cross-sectional and retrospective study on persistent or recurrent cases of TIO followed in referral centers for bone diseases; systematic review of the published persistent and recurrent cases of TIO. Data from patients consecutively evaluated in referral Italian centers for bone diseases were collected; a PubMed search on persistent, recurrent and unoperable cases of TIO was carried out. RESULTS: Sixteen patients (mean age at diagnosis 52.5 ± 10.6 years) with persistent (n = 6, 37,5%), recurrent (n = 7, 43.7%) or not operable (n = 3, 18.8%) TIO were described. Delay in diagnosis (2.5 ± 1.3 years) was demonstrated. All patients experienced fragility fractures or pseudofractures and disabling bone and muscle pain. BMD was significantly reduced (mean T-score -2.7 ± 1.7 and -2.7 ± 0.9 at lumbar spine and femoral neck, respectively). Fourteen patients were maintained under therapy with phosphate salts and calcitriol, while in 2 patients therapy with burosumab, an anti-FGF23 antibody, was commenced. CONCLUSION: A significant number of patients with TIO remain either undiagnosed for tumor localization or tumor recur or persist after surgery. These patients with active disease represent possible candidates for burosumab treatment.

High rate of vertebral refracture after vertebroplasty in patients taking glucocorticoids: a prospective two-year study.

OBJECTIVES: To assess vertebral fracture (VFx) occurrence after percutaneous vertebroplasty (PVP) in patients with osteoporosis (OP), primary or secondary to chronic glucocorticoid (GC) therapy. METHODS: Prospective study of a 2-year follow-up. PRIMARY OUTCOME: proportion of patients with new VFx 24 months after PVP. Eligible patients were osteoporotic patients with VFx and pain resistant to conventional therapy, under GC therapy (n=70) or not (n=71), who underwent PVP. X-rays of dorso/lumbar spine were performed before PVP and 12 and 24 months after the procedure. All the patients were given secondary fractures prevention with oral bisphosphonates plus calcium and vitamin D. RESULTS: The two groups were comparable with respect to male to female ratio, age, BMI, pain score, number of prevalent VFx and their score according to Genant, time interval between VFx and PVP, number of VFx that were treated, vitamin D and PTH plasma levels, and bone mineral density at femur sites. The proportion of patients with new VFx was higher at 12 and 24 months in the group taking GC; at 24 months was 44.3% in GC group and 22.6% in non-GC group (RR 1.96; 95% CI 1.19-3.26, p=0.0087). All new VFx were clinically evident. GC-treated patients had more falls than the patients who were not on GC: 43 falls per 100 pts/y and 32 falls per 100 pts/y, respectively (p<0.05); however, only 4 and 6 falls, respectively, caused a VFx (p=NS). Finally, logistic regression model showed that the increased risk of new VFx was associated with GC use (OR 4.53; 95% CI 1.50-13.69, p=0.0073) and low femoral neck T-scores (OR 3.57; 95% CI 1.82-7.02, p=0.0002). CONCLUSIONS: Patients under treatment with GC show a two-fold increased risk of new VFx after PVP with respect to patients with primary OP. This should be weighed in the individual risk/benefit assessment of the procedure.

One year in review 2018: progress in osteoporosis treatment.

Osteoporosis is a generalised bone disease characterised by decreased bone mass and deterioration of bone microarchitecture predisposing to fragility fractures. Bone fractures are a remarkable social and economic health problem, and several studies have been carried out in order to reduce their occurrence. Inhibiting bone resorption and increasing bone formation are the mainstay of treatment, anti-catabolic and anabolic, respectively. This review highlights the most recent advances in osteoporosis and reports the evidence of efficacy and safety of anabolic treatment of osteoporosis, as evaluated by randomised, controlled trials published during 2017. As the most common form of secondary osteoporosis, we will also discuss the 2017 state-of-the-art on pathogenesis and treatment of glucocorticoid-induced osteoporosis.

Underdiagnosis of osteoporotic vertebral fractures in patients with fragility fractures: retrospective analysis of over 300 patients.

Osteoporosis (OP) is a silent disease unless a fracture occurs; it is a major health problem, mainly due to fragility fractures, that occur at vertebral and peripheral sites. Vertebral fractures (VF) are probably the most common fragility fractures, but they go often unrecognized. The main clinical symptoms of VF are acute and chronic back pain, spinal deformity, reduced mobility and impaired quality of life. They are frequently associated with other fragility fractures. We examined 478 patients at our outpatient clinic, who were referred for fragility fracture occurrence. The most common fragility fractures was hip fractures. However, after execution of spine X-rays in patients who had sustained hip fracture, we found that a large proportion of them had VF, which had not been reported in their medical history.

Efficacy of a specific rehabilitation protocol in postural control of a young woman with multiple fragility vertebral fractures: a case report.

The fragility vertebral fractures have a considerable impact on an individual's health-related quality of life due to pain, limitations in activity, social participation, altered mood and balance impairment. Physiotherapy interventions may have an important role in improving quality of life, balance and reducing the fracture risk in people with osteoporotic vertebral fractures. In literature there are only a few studies that examine exercise interventions in osteoporotic populations with vertebral fracture and few studies that examine the effects on balance with instrumental measurements. In this paper we present a case of a woman with fragility vertebral fractures and a related balance impairment and the effects of a specific rehabilitation program using both clinical evaluations that instrumental measurements.

Osteoporosis with vertebral fractures associated with pregnancy: two case reports.

Pregnancy and lactation-associated osteoporosis (PAO) is a rare condition characterized by the occurrence of fragility fractures, most commonly vertebral, in late pregnancy or the early postpartum period. The prevalence, etiology and pathogenesis of this osteoporosis are unknown, although there are several hypotheses attempting to explain the etiopathogenesis of pregnancy associated osteoporosis. In this paper we present two cases of young women who developed severe PAO with vertebral fractures: a 42-year-old woman with a family history of osteoporosis, and a 21-year-old woman affected with myasthenia gravis. The case 1 presented fragility fracture of D12, L2, and L3. She did not have any disease causing osteoporosis. However, she had a positive familial history for osteoporosis and during pregnancy (12th week) she had a detached placenta, so bed rest was prescribed for two months. The case 2 presented multiple vertebral fracture. She was affected by myasthenia gravis, which was diagnosed two years before pregnancy, and treated with corticosteroid. In summary, pregnancy and lactation-induced osteoporosis, although it is a rare disorder, should be kept in mind when pregnant women or women in postpartum period develop persistent back pain and it is important to monitor the patients with risk factors or secondary causes of osteoporosis.

Adverse events during longterm low-dose glucocorticoid treatment of polymyalgia rheumatica: a retrospective study.

OBJECTIVE: To assess the occurrence of adverse events in a cohort of patients with polymyalgia rheumatica (PMR), treated with low-dose glucocorticoids (GC). METHODS: This was a retrospective study by review of medical records. RESULTS: We identified 222 patients who had a mean duration of followup of 60 ± 22 months and a mean duration of GC therapy of 46 ± 22 months. We found that 95 patients (43%) had at least 1 adverse event after a mean duration of GC therapy of 31 ± 22 months and a mean cumulative dose of 3.4 ± 2.4 g. In particular, 55 developed osteoporosis, 31 had fragility fractures; 27 developed arterial hypertension; 11 diabetes mellitus; 9 acute myocardial infarction; 3 stroke; and 2 peripheral arterial disease. Univariate analysis showed that the duration of GC treatment was significantly associated with osteoporosis (p < 0.0001), fragility fractures (p < 0.0001), arterial hypertension (p < 0.005), and acute myocardial infarction (p < 0.05). Cumulative GC dose was significantly associated with osteoporosis (p < 0.0001), fragility fractures (p < 0.0001), and arterial hypertension (p < 0.01). The adverse events occurred more frequently after 2 years of treatment. Multivariate analysis showed that GC duration was significantly associated with osteoporosis (adjusted OR 1.02, 95% CI 1.02-1.05) and arterial hypertension (adjusted OR 1.03, 95% CI 1.01-1.06); GC cumulative dose was significantly associated with fragility fractures (adjusted OR 1.4, 95% CI 1.03-1.8). CONCLUSION: Longterm, low-dose GC treatment of PMR is associated with serious adverse events such as osteoporosis, fractures, and arterial hypertension; these adverse events occur mostly after 2 years of treatment.

A proposal of simple calculation (ERI calculator) to predict the early response to TNF-α blockers therapy in rheumatoid arthritis.

Increasing evidence has been accumulated for treating rheumatoid arthritis (RA) with TNF-α blocking agents. The formulation and definition of an early indicator of patient's reactivity during therapy may be extremely simplified by a mathematical model of clinical response. We analyzed the most significant clinical and laboratory parameters of response of 35 homogeneous patients (30 women, 5 men mean age ± SD: 52.31 ± 12.30 years) treated with adalimumab 40 mg every 2 weeks associated with methotrexate (MTX) 10-15 mg/week and with a stable dosage of steroids for 30 weeks. The over time trend of the studied parameters showed a linear response, which has allowed the realization of a simple mathematical model. The formula derived from this mathematical model was then applied and therefore validated in a group of 121 patients previously treated with several anti-TNF-alpha agents for at least 6 months. We drafted a mathematical model (early response indicator, ERI) that, by using a simple calculation, allows us to identify a high percentage of responder patients after only 2 weeks of treatment. ERI identified a high percentage (88%) of patients responding after only 2 weeks, as was confirmed at weeks 30; the use of ERI calculation after 6 weeks increases the proportion of responding patients to 92% with a percentage of false negatives of only 12%. ERI could be a useful tool to early differentiate the responder from the non-responder patients.

Incident comorbidity among patients with rheumatoid arthritis treated or not with low-dose glucocorticoids: a retrospective study.

OBJECTIVE: To assess the prevalence of comorbidity in a cohort of patients with rheumatoid arthritis (RA), treated or not with low-dose glucocorticoids (GC) and who have been followed for at least 10 years. METHODS: This was a retrospective study by review of medical records. RESULTS: We identified 365 patients: 297 (81.3%) were GC users (4-6 mg methylprednisolone daily) and 68 (18.7%) were nonusers. We found that fragility fractures occurred in 18.2% of GC users and in 6.0% of GC nonusers (p < 0.02); arterial hypertension in 32.3% of GC users and in 10.4% of GC nonusers (p < 0.0005); acute myocardial infarction in 13.1% of GC users and in 1.5% of the nonusers (p < 0.01). Prevalence of diabetes mellitus, cataract, and infections was comparable. We divided GC users into groups of different duration of GC therapy: < 2, 2-5, and > 5 years; the mean duration of GC treatment was 1.3 ± 0.5, 3.6 ± 1.1, and 12.1 ± 5.1 years, respectively. GC treatment for > 5 years was associated with significantly higher prevalence of fragility fractures (26.6%; p < 0.001 vs the other groups), arterial hypertension (36.7%; p < 0.0002 vs nonusers and GC users < 2 years), myocardial infarction (16.1%; p < 0.01 vs nonusers), and infections (9.7%; p < 0.005 vs the other groups). GC treatment for 2-5 years was associated with a significantly higher prevalence of arterial hypertension (30.0%; p < 0.01) compared to nonusers. CONCLUSION: Patients with RA treated with low-dose GC compared to patients never treated with GC show a higher prevalence of fractures, arterial hypertension, myocardial infarction, and serious infections, especially after 5 years of GC treatment. The high prevalence of myocardial infarction and fractures in patients with RA suggests that a more accurate identification of risk factors and prevention measures should be adopted when longterm GC treatment is needed.

Effect of low dose methotrexate on bone density in women with rheumatoid arthritis: results from a multicenter cross-sectional study.

OBJECTIVE: To analyze the influence of low dose methotrexate (MTX) on bone using data from a large multicenter, cross-sectional study on bone mineral density (BMD) in women with rheumatoid arthritis (RA). METHODS: We selected 731 female patients with RA divided into 2 groups on the basis of MTX use: never MTX users (n = 485) and MTX users for at least 6 months (n = 246). Demographic, disease, and treatment related variables were collected for each patient. BMD was measured at lumbar spine and proximal femur by dual energy x-ray absorptiometry. Osteoporosis was defined as BMD < -2.5 T-score. RESULTS: The frequency of osteoporosis among never MTX users and MTX users was 29.1% and 28.3% (p = NS) for lumbar spine, and 34.8% and 37.8% (p = NS) for femoral neck, respectively. Mean T-score values at lumbar spine and femoral neck were comparable in the 2 groups, even after adjusting for age, menopausal status, body mass index (BMI), Health Assessment Questionnaire (HAQ) score, and steroid use. The generalized linear model showed that age, menopause, BMI, HAQ score, and steroid use were significant independent predictors of BMD at lumbar or at femoral level, whereas MTX use was not. Logistic procedure showed that only age, HAQ score, and BMI were significantly associated with the risk of osteoporosis. CONCLUSION: We found no negative effect of low dose MTX on BMD in women with RA.

Single infusion of neridronate (6-amino-1-hydroxyhexylidene-1,1-bisphosphonate) in patients with active rheumatoid arthritis: effects on disease activity and bone resorption markers.

AIMS: The aim of this study was to assess the effects of a single infusion of the bisphosphonate neridronate (N) on parameters of inflammation and bone resorption in rheumatoid arthritis (RA). METHODS: Forty-five patients with active RA were randomly allocated on a double blind basis to receive a single intravenous infusion of either N 25 mg (15 patients), N 50 mg (15 patients), or placebo (15 patients). At baseline and after 7 and 21 days, we assessed the following: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and Ritchie's articular index as indices of disease activity; and urinary free deoxypyridinoline (DPyr), N-telopeptide of type I collagen (NTx) and hydroxyproline (OHP) as indices of bone resorption. RESULTS: At day 7, N 25 mg significantly decreased ESR compared to N 50 mg (p=0.002), and CRP compared to placebo (p=0.036). With regard to bone resorption markers, at day 7, both N 25 mg and 50 mg compared to placebo significantly decreased NTx (p<0.0005 and p=0.003, respectively) and OHP (p=0.001 and p=0.004, respectively). At day 21, N 50 mg significantly decreased OHP compared to placebo (p=0.017). DPyr levels remained unchanged in the three groups. CONCLUSIONS: N 25 mg and 50 mg exerted different effects on RA activity parameters, since only the lower dose significantly decreased ESR and CRP. Both doses of N inhibited bone resorption, with a transient, significant reduction in urinary NTx and OHP, but without any effect on DPyr.