Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment. METHODS: We randomised 222 individuals at increased risk of PDB because of pathogenic SQSTM1 variants to receive 5 mg zoledronic acid (ZA) or placebo. The primary outcome was new bone lesions assessed by radionuclide bone scan. Secondary outcomes included change in existing lesions, biochemical markers of bone turnover and skeletal events related to PDB. RESULTS: The median duration of follow-up was 84 months (range 0-127) and 180 participants (81%) completed the study. At baseline, 9 (8.1%) of the ZA group had PDB lesions vs 12 (10.8%) of the placebo group. Two of the placebo group developed new lesions versus none in the ZA group (OR 0.41, 95% CI 0.00 to 3.43, p=0.25). Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003). At the study end, 1 participant in the ZA group had lesions compared with 11 in the placebo group. Biochemical markers of bone turnover were significantly reduced in the ZA group. One participant allocated to placebo required rescue therapy with ZA because of symptomatic disease. The number and severity of adverse events did not differ between groups. CONCLUSIONS: Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

A Prospective Open-Label Observational Study of a Buffered Soluble 70 mg Alendronate Effervescent Tablet on Upper Gastrointestinal Safety and Medication Errors: The GastroPASS Study.

Upper gastrointestinal (GI) side effects are a main reason for discontinuing bisphosphonate treatment, an important therapeutic option for osteoporosis patients. Consequently, the development of novel formulations with improved tolerability is warranted. In this multicenter prospective, observational, postauthorization safety study conducted in Italy and Spain, postmenopausal women (PMW) with osteoporosis (naïve to bisphosphonates) were treated weekly with a buffered soluble alendronate 70 mg effervescent (ALN-EFF) tablet (Binosto®) and followed for 12 ± 3 months. Information was collected on adverse events (AEs), medication errors, persistence, and compliance using the Morisky-Green questionnaire. Patients (N = 1028) aged 67 ± 9 years (mean ± SD) received ALN-EFF weekly. The cumulative incidence of upper GI AEs (oesophageal toxicity, gastritis, gastric ulcers, and duodenitis) related to ALN-EFF (primary endpoint) was 9.6% (95% confidence interval [CI] 7.9-11.6%), the vast majority being of mild intensity. The most frequently occurring upper GI AEs related to ALN-EFF were dyspepsia (2.7%), gastroesophageal reflux disease (2.4%), and nausea (2.2%). None of the relevant upper GI AEs listed in the primary endpoint and no serious AEs were reported. At least one medication error occurred in 29.9% (95% CI 27.1-32.8%) of patients. However, the majority of medication errors were associated with administration instructions applicable to any oral bisphosphonate and only seven medication errors were associated with the ALN-EFF formulation. ALN-EFF was discontinued in 209 of 1028 (20.3%) patients. The most frequent reasons for discontinuation were AEs related to ALN-EFF (46.9%) and patients' decision (42.6%). Compliance with ALN-EFF was high, reflected by a mean Morisky-Green score of 92.8 ± 18.6. PMW with osteoporosis treated with ALN-EFF in a real-world setting experienced few upper GI AEs. In addition, they had a low discontinuation and high compliance compared with other formulations, suggesting that ALN-EFF may increase patient satisfaction and therefore long-term adherence and efficacy. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Influence of anti-osteoporosis treatments on the incidence of COVID-19 in patients with non-inflammatory rheumatic conditions.

Coronavirus disease 19 (COVID-19) is currently a global pandemic that affects patients with other pathologies. Here, we investigated the influence of treatments for osteoporosis and other non-inflammatory rheumatic conditions, such as osteoarthritis and fibromyalgia, on COVID-19 incidence. To this end, we conducted a cross-sectional study of 2,102 patients being treated at the Rheumatology Service of Hospital del Mar (Barcelona, Spain). In our cohort, COVID-19 cumulative incidence from March 1 to May 3, 2020 was compared to population estimates for the same city. We used Poisson regression models to determine the adjusted relative risk ratios for COVID-19 associated with different treatments and comorbidities. Denosumab, zoledronate and calcium were negatively associated with COVID-19 incidence. Some analgesics, particularly pregabalin and most of the studied antidepressants, were positively associated with COVID-19 incidence, whereas duloxetine presented a negative association. Oral bisphosphonates, vitamin D, thiazide diuretics, anti-hypertensive drugs and chronic non-steroidal anti-inflammatory drugs had no effect on COVID-19 incidence in the studied population. Our results provide novel evidence to support the maintenance of the main anti-osteoporosis treatments in COVID-19 patients, which may be of particular relevance to elderly patients affected by the SARS-CoV-2 pandemic.

The next step after anti-osteoporotic drug discontinuation: an up-to-date review of sequential treatment.

Several antiresorptive drugs, like bisphosphonates and denosumab, are currently available for the treatment of osteoporosis due to their evidenced efficacy in reducing fracture risk at mid-term. Osteoanabolic therapies, like teriparatide, whose treatment duration is limited to 2 years, have also shown efficacy in the reduction of fracture risk. However, depending on the severity of osteoporosis and the presence of other associated risk factors for fracture, some patients may require long-term treatment to preserve optimal bone strength and minimize bone fracture risk. Given the limited duration of some treatments, the fact that most of the antiresorptive drugs have not been assessed beyond 10 years, and the known long-term safety issues of these drugs, including atypical femoral fractures or osteonecrosis of the jaw, the long-term management of these patients may require an approach based on drug discontinuation and/or switching. In this regard, interest in sequential osteoporosis therapy, wherein drugs are initiated and discontinued over time, has grown in recent years, although the establishment of an optimal and individualized order of therapies remains controversial. This review reports the currently available clinical evidence on the discontinuation effects of different anti-osteoporotic drugs, as well as the clinical outcomes of the different sequential treatment regimens. The objective of this article is to present up-to-date practical knowledge on this area in order to provide guidance to the clinicians involved in the management of patients with osteoporosis.

Revisión de la evidencia científica sobre uso clínico del Trabecular Bone Score (TBS) Posiciones oficiales de la SEIOMM (2018) / No disponible

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Self-reported screening questionnaire for the assessment of Joint Hypermobility Syndrome (SQ-CH), a collagen condition, in Spanish population

Background and Objectives: To develop a self-assessment screening questionnaire (SQ-CH), with image illustrated criteria to easily identify collagen anomalies and to assist Hypermobility's evaluation in a Spanish sample. Methods: One hundred ninety one participants were recruited form an anxiety outpatient unit of a general university hospital and from a primary care setting, underwent a complete and rigorous evaluation of hypermobility. First, all participants completed the self-reported measures for the screening of Hypermobility Syndrome, the 7 self-reported items in y/n format aiming to validate (SQ-CH) and the 5 item self-reporting questionnaire of Hakim and Grahame (2003). Secondly, each of the participants was individual assessed by a trained clinician on the Beighton and Hospital del Mar evaluation for the diagnosis of Joint Hypermobility Syndrome. Results: Significant correlations were found between the SQ-CH and the Beighton and Hospital del Mar scales as well as with the 5-item self-reporting questionnaire. Results on temporal stability, specificity and sensitivity of the SQ-CH were satisfactory, and the best cut-off point was set at 3 positive items (i.e. answered affirmatively). Conclusions: The developed screening questionnaire for hypermobility (SQ-CH) is, to our knowledge, the first self-assessment questionnaire to evaluate the symptoms of the joint hypermobility syndrome in a Spanish population. It has shown good validity and good reliability and is therefore ready for its use as a screening tool to assess this collagen condition in all sort of potential suffers, particularly, patients suffering from anxiety (AU)

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Osteopoiquilia con afectación de la columna vertebral, una presentación atípica / Osteopoikilosis with involvement of the spine, an atypical presentation

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Screening for the presence of FMR1 premutation alleles in women with fibromyalgia.

Fibromyalgia is a chronic condition characterized by widespread pain, fatigue, non-restorative sleep and cognitive difficulties that affects 2-4% of the general population. Recently a possible relationship between the FMR1 premutation and fibromyalgia has been pointed out. In attempt to gather more data we screened for the FMR1 CGG expansion 700 DNA samples from unrelated fibromyalgia patients. This data might be useful for evaluating the incorporation of this test in rheumatologic procedures for women with fibromyalgia. The observed frequency of FMR1 premutation carriers (3 of 700, 0.4%) is not significantly different from the estimated rate in the general female population (1/250-1/400) (P=0.539, P=0.716). Clinical examination of the FMR1 premutation carriers identified revealed that all of them had important neurological symptoms with regard to muscular symptoms, neurocognitive alterations and neurovegetative impairments. With regard to other clinical aspects of the disease the cases apparently did not differ from the average fibromyalgia patients. On the basis of our results an FMR1 screening among fibromyalgia female patients would not be recommended. However it would be worthwhile to further evaluate the different clinical presentations that fibromyalgia patients might present based on their FMR1 premutation carrier status.

Comparison of the effects of ossein-hydroxyapatite complex and calcium carbonate on bone metabolism in women with senile osteoporosis: a randomized, open-label, parallel-group, controlled, prospective study.

BACKGROUND AND OBJECTIVE: Calcium and vitamin D supplementation is recommended in patients with osteopenia and osteoporosis. One group that could benefit from this treatment is women with senile osteoporosis. Two sources of supplementary calcium are ossein-hydroxyapatite complex (OHC) and calcium carbonate, but, to date, their comparative effects on bone metabolism have not been studied in women with senile osteoporosis. The objective of this study was to compare the effects of OHC and calcium carbonate on bone metabolism in women with senile osteoporosis. METHODS: This was a randomized, open-label, parallel-group, controlled, prospective study to compare the effects of OHC (treatment group) and calcium carbonate (control group) on bone metabolism. Patients were included between 2000 and 2004 and followed up for a maximum of 3 years. The study was carried out at the bone metabolism unit of two university hospitals in Barcelona, Spain. Subjects were women aged >65 years with densitometric osteoporosis of the lumbar spine or femoral neck. The treatment group received open-label OHC (Osteopor®) at a dose of two 830 mg tablets every 12 hours (712 mg elemental calcium per day). The control group received open-label calcium carbonate at a dose of 500 mg of elemental calcium every 12 hours (1000 mg elemental calcium per day). Both groups also received a vitamin D supplement (calcifediol 266 µg) at a dose of one vial orally every 15 days. Biochemical markers of bone remodelling (osteocalcin by electrochemiluminescence, tartrate-resistant acid phosphatase using colorimetry) were measured at baseline and annually for 3 years. Bone mineral density (BMD) at the lumbar spine and femoral neck was also measured. RESULTS: One hundred and twenty women were included (55 in the OHC group and 65 in the calcium carbonate group), of whom 54 completed 3 years of follow-up. Levels of serum osteocalcin increased to a greater extent in the OHC group compared with the calcium carbonate group (by a mean ± SD of 0.84 ± 3.13 ng/mL at year 2 and 1.86 ± 2.22 ng/mL at year 3 in the OHC group compared with a mean ± SD decrease of 0.39 ± 1.39 ng/mL at year 2 and an increase of 0.31 ± 2.51 ng/mL at year 3 in the calcium carbonate group); the differences between treatment groups were statistically significant (p < 0.05) at both years. Changes over time in serum osteocalcin level were also statistically significant (p < 0.05) in the OHC group, but not in the calcium carbonate group. Changes in mean BMD at the lumbar spine and femoral neck between baseline and year 3 were -1.1% and 2.5% for OHC and -2.3% and 1.2% for calcium carbonate, respectively. CONCLUSION: OHC had a greater anabolic effect on bone than calcium carbonate.

Melorreostosis: presentación de un caso y revisión de la literatura / Melorheostosis, a case report

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Calcium citrate and vitamin D in the treatment of osteoporosis.

The combination of calcium with vitamin D (vitamin D(3) [colecalciferol]) forms the basis of preventive and therapeutic regimens for osteoporosis. A number of studies have suggested that the combination of calcium and vitamin D is effective when administered at respective dosages of at least 1200 mg and 800 IU per day, although efficacy is, as expected, affected by patient compliance. Overall, treatment with this combination appears to be effective in reducing the incidence of non-vertebral and hip fractures. Also, in all drug studies (of antiresorptive and anabolic agents and strontium ranelate) that demonstrated a reduction in risk of osteoporotic fractures, patients also took calcium and vitamin D supplements. An important finding in this regard is that vitamin D levels have been demonstrated to be inadequate in more than half of women treated for osteoporosis in the US and Europe. The capacity of the small intestine to absorb calcium salts depends on the solubility and ionization of the salts. These properties vary for different salts, with fasting calcium citrate absorption being greater than that of calcium lactogluconate and calcium carbonate. Calcium citrate formulations taken between meals may help to prevent abdominal distension and flatulence, as well as minimize the risk of renal calculus formation, thus helping to optimize patient compliance. Therefore, calcium citrate combined with vitamin D is the combination of choice for the prevention or treatment of osteoporosis.

Reduced proliferation and osteocalcin expression in osteoblasts of male idiopathic osteoporosis.

Osteoporosis is characterized by low bone mineral density (BMD), resulting in increasing susceptibility to bone fractures. In men, it has been related to some diseases and toxic habits, but in some instances the cause of the primary--or idiopathic--osteoporosis is not apparent. In a previous study, our group compared histomorphometric measurements in cortical and cancellous bones from male idiopathic osteoporosis (MIO) patients to those of control subjects and found reduced bone formation without major differences in bone resorption. To confirm these results, this study analyzed the etiology of this pathology, examining the osteoblast behavior in vitro. We compared two parameters of osteoblast activity in MIO patients and controls: osteoblastic proliferation and gene expression of COL1A1 and osteocalcin, in basal conditions and with vitamin D(3) added. All these experiments were performed from a first-passage osteoblastic culture, obtained from osteoblasts that had migrated from the transiliac explants to the plate. The results suggested that the MIO osteoblast has a slower proliferation rate and decreased expression of genes related to matrix formation, probably due to a lesser or slower response to some stimulus. We concluded that, contrary to female osteoporosis, in which loss of BMD is predominantly due to increased resorption, low BMD in MIO seems to be due to an osteoblastic defect.

Efficacy of ossein-hydroxyapatite complex compared with calcium carbonate to prevent bone loss: a meta-analysis.

OBJECTIVE: There is increasing evidence to suggest that ossein-hydroxyapatite complex (OHC) is more effective than calcium supplements in maintaining bone mass. The aim of this meta-analysis was to determine whether OHC has a different clinical effect on bone mineral density (BMD) compared with calcium carbonate (CC). METHODS: A meta-analysis of randomized controlled clinical trials was carried out to evaluate the efficacy of OHC versus CC on trabecular BMD. We identified publications on clinical trials by a search of electronic databases, including MEDLINE (1966-November 2008), EMBASE (1974-November 2008), and the Cochrane Controlled Clinical Trials Register.The primary endpoint was percent change in BMD from baseline. Data were pooled in a random-effects model, and the weighted mean difference was calculated. A sensitivity analysis that excluded trials without full data was performed. RESULTS: Of the 18 controlled trials initially identified, 6 were included in the meta-analysis. There was no significant heterogeneity among the included trials. The percent change in BMD significantly favored the OHC group (1.02% [95% CI, 0.63-1.41], P < 0.00001). These results were confirmed in the sensitivity analysis. CONCLUSIONS: OHC is significantly more effective in preventing bone loss than CC.

Bone histomorphometry in 22 male patients with normocalciuric idiopathic osteoporosis.

Osteoporosis is associated with increased bone resorption together with a decrease in bone formation. In women, there is an increase of resorption surfaces and in the number of osteoclasts. These changes, however, are not found in males. This purpose of this study was to examine clinical, laboratory, and histomorphometric data in a series of 22 male patients with primary osteoporosis and normocalciuria undergoing transiliac bone biopsy. All of them gave written informed consent for bone biopsy. Automated biochemical profile, urinary calcium excretion, and bone marker assays were performed. Histomorphometric studies were carried out in transiliac bone biopsies obtained with a Bordier-Lepine needle with previous tetracycline labeling. The histomorphometric values of cancellous bone showed significantly lower values of bone volume and values of osteoid surface (OS/BS) and osteoblast surface (Ob.S/BS), and a modest increase in osteoid thickness (O.Th) without changes in the mineralization lag time or eroded surface in patients compared with controls. In cortical bone, there was a low cortical volume (Ct.V/TV) and cortical width (Ct.Wi) in patients compared with controls, without differences in cortical porosity (Po.V/TV). These results suggest that normocalciuric idiopathic osteoporosis in men is characterized by decreased cancellous osteoblasts and bone turnover.