Long-term follow-up of severe autosomal recessive SP7-related bone disorder.

The SP7 gene encodes a zinc finger transcription factor (Osterix), which is a member of the Sp subfamily of sequence-specific DNA-binding proteins, playing an important role in osteoblast differentiation and maturation. SP7 pathogenic variants have been described in association with different allelic disorders. Monoallelic or biallelic SP7 variants cause Osteogenesis imperfecta type XII (OI12), a very rare condition characterized by recurrent fractures, skeletal deformities, undertubulation of long bones, hearing loss, no dentinogenesis imperfecta, and white sclerae. Monoallelic or biallelic SP7 variants may also cause sclerotic skeletal dysplasias (SSD), partially overlapping with Juvenile Paget's disease and craniodiaphyseal dysplasia, characterized by skull hyperostosis, long bones sclerosis, large ribs and clavicles, and possible recurrent fractures. Here, we report the long-term follow-up of an 85-year-old woman presenting with a complex bone disorder including features of either OI12 (bone fragility with multiple fractures, severe deformities and short stature) or SSD (striking skull hyperostosis with optic atrophy, very large ribs and clavicles and long bones sclerosis). Exome sequencing showed previously undescribed biallelic loss of function variants in the SP7 gene: NM_001173467.2(SP7): c.359_362del, p.(Asp120Valfs*11); NM_001173467.2(SP7): c.1163_1174delinsT, p.(Pro388Leufs*33). RT-qPCR confirmed a severely reduced SP7 transcription compared to controls. Our report provides new insights into the clinical and molecular features and long-term outcome of SP7-related bone disorders (SP7-BD), suggesting a continuum phenotypic spectrum characterized by bone fragility, undertubulation of long bones, scoliosis, and very heterogeneous bone mineral density ranging from osteoporosis to osteosclerosis.

Reassuring Data on the Cardiovascular Risk in Adults With X-linked Hypophosphatemia Receiving Conventional Therapy.

CONTEXT: X-linked hypophosphatemia (XLH) is a rare genetic disorder that results in increased plasma levels of fibroblast growth factor 23 (FGF23). Several studies have demonstrated a direct association between FGF23 and cardiovascular mortality in cohorts of patients with chronic renal failure. However, in patients with XLH, studies on the cardiovascular impact of the disease are rare, with contradictory results. OBJECTIVE: The aim was to assess whether the disease led to an increased cardiovascular risk. METHODS: We conducted a single-center retrospective observational study on a local cohort of adult patients with XLH. The primary endpoint was a composite endpoint of the frequency of left ventricular hypertrophy (LVH) or presence of high blood pressure. Our secondary objectives were to assess echocardiographic, pulse wave velocity, and central blood pressure data as other markers of CV health. Independently of this cohort, tissue sodium content with magnetic resonance imaging was studied in 2 patients with XLH before and after burosumab. RESULTS: Twenty-two patients were included. Median serum phosphate was 0.57 (0.47-0.72) mmol/L and FGF23 94 pg/L (58-2226). Median blood pressure was 124 (115-130)/68 (65-80) mm Hg, with only 9% of patients being hypertensive. A majority of patients (69%) had no LVH, only 1 had a left ventricular mass >100 g/m² and 25% of patients had left ventricular remodeling. Pulse wave velocity was normal in all patients. No differences in skin and muscle sodium content were observed before and after burosumab in the 2 patients who underwent sodium magnetic resonance imaging. CONCLUSION: We found no elevated risk of developing hypertension or LVH in patients with XLH.

Dysregulation of MicroRNAs in Adult Osteogenesis Imperfecta: The miROI Study.

As epigenetic regulators of gene expression, circulating micro-RiboNucleic Acids (miRNAs) have been described in several bone diseases as potential prognostic markers. The aim of our study was to identify circulating miRNAs potentially associated with the severity of osteogenesis imperfecta (OI) in three steps. We have screened by RNA sequencing for the miRNAs that were differentially expressed in sera of a small group of OI patients versus controls and then conducted a validation phase by RT-qPCR analysis of sera of a larger patient population. In the first phase of miROI, we found 79 miRNAs that were significantly differentially expressed. We therefore selected 19 of them as the most relevant. In the second phase, we were able to validate the significant overexpression of 8 miRNAs in the larger OI group. Finally, we looked for a relationship between the level of variation of the validated miRNAs and the clinical characteristics of OI. We found a significant difference in the expression of two microRNAs in those patients with dentinogenesis imperfecta. After reviewing the literature, we found 6 of the 8 miRNAs already known to have a direct action on bone homeostasis. Furthermore, the use of a miRNA-gene interaction prediction model revealed a 100% probability of interaction between 2 of the 8 confirmed miRNAs and COL1A1 and/or COL1A2. This is the first study to establish the miRNA signature in OI, showing a significant modification of miRNA expression potentially involved in the regulation of genes involved in the physiopathology of OI. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Osteogenesis Imperfecta: characterization of fractures during pregnancy and post-partum.

BACKGROUND: Pregnancy and breastfeeding are associated with bone density loss. Fracture occurrence during pregnancy and post-partum, and its determinants, remain poorly known in Osteogenesis Imperfecta (OI). The aim of this study was to characterize fractures that occurred during pregnancy and post-partum in OI patients. RESULTS: We conducted a retrospective multicentric study including a total of 50 previously pregnant OI women from 10 Bone Centers in France. Among these patients, 12 (24%) patients experienced fractures during pregnancy or in the 6 months following delivery, and 38 (76%) did not experience any fracture. The most frequent localizations were: proximal femur (25%), spine (25%), distal femur (12.5%), and pelvis (12.5%). Fractures during pregnancy occurred during the third trimester and post-partum fractures occurred with a mean delay of 2 months following delivery. No fractures occurred during childbirth. We next compared the 12 patients with pregnancy or post-partum fractures with the 38 patients without fractures. Mean age at pregnancy was 32.7 ± 3.1 years-old in the fractured group, vs 29.3 ± 5.0 years-old in the non-fractured group (p = 0.002). Breastfeeding was reported in 85.7% of patients in the fractured group, vs 47.1% in the non-fractured group (p = 0.03). All patients with post-partum fractures were breastfeeding. Bone mineral density was significantly lower in patients with pregnancy-related fractures compared with other patients: spine Z-score - 2.9 ± 1.6DS vs - 1.5 ± 1.7DS (p = 0.03), and total hip Z-score - 2.0 ± 0.7DS vs - 0.5 ± 1.4DS (p = 0.04). At least one osteoporosis-inducing risk factor or disease other than OI was identified in 81.8% vs 58.6% of fractured vs non-fractured patients (not significant). Fracture during pregnancy or post-partum was not associated with the severity of OI. Bisphosphonates before pregnancy were reported in 16.7% and 21.1% of patients with pregnancy-related fractures and non-fractured patients, respectively (not significant). CONCLUSIONS: OI management during pregnancy and post-partum should aim for optimal control of modifiable osteoporosis risk factors, particularly in patients with low BMD. Breastfeeding should be avoided.

Genetic testing is useful in adults with limited phenotypes of genetic skeletal conditions.

We show the value of genetic screening in 3 adults with limited phenotypes of three bone sclerosing genetic disease (GD): osteopetrosis (OPT), Camurati-Engelmann disease (CED) and pycnodysostosis. INTRODUCTION: OPT, CED and pycnodysostosis are three rare bone diseases often diagnosed in childhood. However, some atypical phenotypes raise the problem of delayed diagnosis in adults. Genetic tests may then be useful to establish a formal diagnosis. METHODS: We report 3 cases of adult patients with symptomatic or asymptomatic bone sclerosing lesions for whom the clinical, radiological and biological explorations were atypical and did not allow a formal diagnosis. These unusual descriptions led to the search for genetic mutations. RESULTS: These 3 cases of limited phenotypes were associated with unknown or poorly described variants of 3 rare bone genetic diseases. CONCLUSIONS: Genetic tests proved useful to establish the diagnosis and manage the condition of adults with rare bone sclerosing GD.

The QUALYOR (QUalité Osseuse LYon Orléans) study: a new cohort for non invasive evaluation of bone quality in postmenopausal osteoporosis. Rationale and study design.

The diagnostic performance of densitometry is inadequate. New techniques of non-invasive evaluation of bone quality may improve fracture risk prediction. Testing the value of these techniques is the goal of the QUALYOR cohort. INTRODUCTION: The bone mineral density (BMD) of postmenopausal women who sustain osteoporotic fracture is generally above the World Health Organization definition for osteoporosis. Therefore, new approaches to improve the detection of women at high risk for fracture are warranted. METHODS: We have designed and recruited a new cohort to assess the predictive value of several techniques to assess bone quality, including high-resolution peripheral quantitative computerized tomography (HRpQCT), hip QCT, calcaneus texture analysis, and biochemical markers. We have enrolled 1575 postmenopausal women, aged at least 50, with an areal BMD femoral neck or lumbar spine T-score between - 1.0 and - 3.0. Clinical risk factors for fracture have been collected along with serum and blood samples. RESULTS: We describe the design of the QUALYOR study. Among these 1575 women, 80% were aged at least 60. The mean femoral neck T-score was - 1.6 and the mean lumbar spine T-score was -1.2. This cohort is currently being followed up. CONCLUSIONS: QUALYOR will provide important information on the relationship between bone quality variables and fracture risk in women with moderately decreased BMD.

Effects of oral alendronate on BMD in adult patients with osteogenesis imperfecta: a 3-year randomized placebo-controlled trial.

UNLABELLED: A 3-year, randomized, double-blind, placebo-controlled trial evaluated the effect of oral alendronate on the BMD of 64 adult patients with osteogenesis imperfecta. The mean increases in the lumbar spine BMD were 10.1 +/- 9.8% (p < 0.001) and 0.7 +/- 5.7% in the alendronate and placebo groups, respectively. Oral alendronate increases BMD in adult patients with osteogenesis imperfecta. INTRODUCTION: This study evaluated the effect of oral alendronate on the BMD of adult patients with osteogenesis imperfecta. MATERIALS AND METHODS: We carried out a 3-year, randomized, double-blind, placebo-controlled trial of oral alendronate in 64 adult patients with osteogenesis imperfecta. The primary endpoint was the difference between the groups in the mean percent change in lumbar spine BMD at 3 years. Secondary outcomes included changes in BMD of total hip, vertebral and peripheral fracture incidence, pain, hearing loss, and bone turnover biochemical markers. Patients were treated daily with either placebo or 10 mg alendronate. All received 1 g of calcium and 800 IU of vitamin D daily. RESULTS: The mean +/- SD increases in the lumbar spine BMD were 10.1 +/- 9.8% (p < 0.001) and 0.7 +/- 5.7% in the alendronate and placebo groups, respectively. Hip BMD increased in the alendronate group by 3.3 +/- 0.5% (p = 0.001) and decreased in the placebo group by 0.3 +/- 0.6%. The sample size was not sufficient to determine an effect of alendronate on fracture rate. A significant increase of the pain score was noted in the alendronate group (p = 0.04) in the intent-to-treat analysis but not in the per protocol analysis. There was no change in hearing in either group. Bone resorption and formation biochemical markers were significantly decreased in the alendronate group (p < 0.001). There were no differences in severe adverse effects between the groups, but there was an increase in nonsevere upper gastrointestinal effects in the alendronate group (p = 0.003). CONCLUSIONS: Oral alendronate increases BMD and increase nonsevere gastrointestinal adverse effects but does not modify the hearing loss in adult patients with osteogenesis imperfecta. More studies are needed to evaluate an effect on the fracture rate.

Fluoride exposure and bone status in patients with chronic intestinal failure who are receiving home parenteral nutrition.

BACKGROUND AND OBJECTIVE: Metabolic bone disease is frequent in chronic intestinal failure. Because fluoride has a major effect on bones, the status of both fluoride and bone was studied in long-term home parenteral nutrition (HPN) patients. DESIGN: We studied 31 adults aged (x +/- SD) 56.3 +/- 15.1 y, mainly patients with short-bowel syndrome, who had been receiving HPN for >1 y. Bone mineral density (BMD) was measured by absorptiometry, and serum fluoride was measured by using a fluoride-sensitive electrode. All patients ate and drank ad libitum. HPN (3.4 +/- 1.2 times/wk) complemented oral nutrition. Potential explicative factors were estimated by using a linear regression model (mixed-effects model). RESULTS: Of 120 fluoride dosages (2-6/patient), 102 were above the upper normal limit (1.58 micromol/L) at the laboratory. Mean (+/- SD) daily fluoride supply was 8.03 +/- 7.71 mg (US adequate intake: 3.1 mg/d for women and 3.8 for men; tolerable upper normal limit: 10 mg/d); intravenous fluoride varied from 0.06 to 1.45 mg, and oral fluoride varied from 0.09 to 27.8 mg. Serum fluoride concentrations were correlated with creatinine clearance and fluoride supply. BMD was significantly lower in the femoral neck than in the spinal area. After adjustment for sex and the duration of HPN, only the effect of serum fluoride on spinal BMD was significant. Two patients had symptoms of fluorosis, eg, calcaneum fissures, interosseous calcifications, or femoral neck osteoporosis. CONCLUSIONS: In chronic intestinal failure, high intakes of fluoride are frequent because of the beverages ingested to compensate for stool losses. Hyperfluoremia has an effect on bone metabolism and may increase skeletal fragility. The consumption of fluoride-rich beverages for extended periods is therefore not advisable.

Osteoporosis and breast cancer.

Osteoporosis affects one in three women after the menopause and the incidence of osteoporotic fractures increases steadily throughout life. Breast cancer is the most common cancer in women, both before and after the menopause. In younger women, recovery from breast cancer has been achieved using aggressive chemotherapy and radiotherapy that can adversely affect bone tissue or induce premature menopause. In postmenopausal women, breast cancer and osteoporosis are common, and although both are dependent on estrogens this leads to conflicting implications for the diagnosis and treatment: estrogens reduce the risk of fractures but increase the risk of breast cancer. Estrogen supplementation is, therefore, contraindicated in patients with a history of breast cancer. Selective estrogen response modifiers (SERMs) hold great promise, as they decrease both the fracture risk via an estrogen-agonist effect on bone and the breast cancer risk via an estrogen-antagonist effect on the breast tissue. SERMs can be used after successful treatment for breast cancer. Bisphosphonates, which are potent bone resorption inhibitors, are widely used both in cancer patients and in the prevention and treatment of spinal and peripheral osteoporotic fractures. Contraindications are exceedingly rare, and the satisfactory safety profile of these agents can be expected to improve further with newly developed modes of administration. Whether the bisphosphonates currently used to treat osteoporosis (alendronate and risendronate) have beneficial effects on skeletal events related to cancer progression remains to be determined, however. In sum, selection of the optimal treatment for osteoporosis in a patient with breast cancer involves assessment of the risk/benefit ratio of each treatment option, based on patient age, other risk factors for osteoporosis, and the stage of breast cancer progression.