Renal tubular acidosis, Sjögren syndrome, and bone disease

BACKGROUND: There has been disagreement about whether osteomalacia (adult rickets) occurs in adults with type 1 (distal) renal tubular acidosis (RTA1). Therefore, after finding scapular pseudofractures in a patient with RTA1 and Sj?gren syndrome, we decided to survey other patients with RTA to learn whether osteomalacia occurred in others and, if it did, whether it was necessarily associated with the presence of Sj?gren syndrome. METHODS: We examined the hospital records and laboratory findings of 250 patients with codes for RTA, 124 with codes for osteomalacia, and 20 with codes for Sj?gren syndrome who were seen at a university-affiliated acute care municipal hospital since 1990. Further detailed survey was then limited to patients older than 15 years and excluded those with potentially confounding causes of bone disease such as chronic renal insufficiency or sickle cell disease. Seven adults with RTA1 were thereby identified. RESULTS: Two adults with RTA1 had radiological and biochemical findings compatible with osteomalacia, and 1 had findings compatible with Sj?gren syndrome. A third patient without Sj?gren syndrome had biochemical findings suggestive of osteomalacia. CONCLUSIONS: Osteomalacia seems to occur in some adult patients with RTA1, and not only in association with Sj?gren syndrome. We found no biochemical evidence of osteomalacia in the patients with Sj?gren syndrome who did not have RTA.     

Statins, fracture risk, and bone remodeling: What is true?

Besides the action on plasma lipid levels, statins show a series of ancillary effects defined as all of their vascular and nonvascular effects independent from the cholesterol reduction. It has been recently hypothesized that one of these ancillary effects could be the improvement of bone health, due to the interference with bone metabolism. This may potentially represent the rationale for statins' use in the treatment of osteoporosis, the most common disease of the bone. Both experimental observations and clinical studies on this topic generated a number of conflicting results; however, the largest randomized clinical trials, the Scandinavian Simvastatin Survival Study (4S), Long Term Intervention with Pravastatin in Ischemic Disease (LIPID), and Heart Protection Study (HPS), indicate that statins do not prevent or reduce fracture risk.     

Adult bone marrow–derived cells: Regenerative potential, plasticity, and tissue commitment

Reconstitution of infarcted myocardium with functional new cardiomyocytes and vessels, a goal that only a few years ago would have been regarded as extravagant, is now actively pursued in numerous laboratories and clinical centers. Several recent studies in animals as well as humans have shown that transplantation of adult bone marrow-derived cells (BMCs) can improve left ventricular function and halt adverse remodeling after myocardial infarction. Differentiation of adult BMCs into cells of cardiac and vascular lineages has been proposed as a mechanism underlying these benefits and, indeed, differentiation of adult BMCs into cells of non-hematopoietic lineages, including cells of brain, skeletal muscle, heart, liver, and other organs, has been documented repeatedly both in vitro and in vivo. These results are in contrast with conventional definitions and dogma, according to which adult tissue-specific stem cells exhibit only restricted differentiation potential. Thus, these recent studies have sparked intense debate over the ability of adult BMCs to differentiate into non-hematopoietic tissues, and the regeneration of myocardium by differentiation of adult BMCs remains highly controversial. Because of the enormous clinical implications of BMC-mediated cardiac repair, numerous laboratories are currently addressing the feasibility of cardiac regeneration with BMCs and deciphering the mechanism underlying the beneficial effects. The purpose of this review is to critically examine the available evidence regarding the ability of adult BMCs to regenerate non-hematopoietic tissues and their utility in therapeutic cardiac regeneration.     

What is the role of DXA, QUS and bone markers in fracture prediction, treatment allocation and monitoring?

There is evidence that treatment can decrease the risk of fractures in osteoporotic patients, and screening of these patients is therefore relevant. Diagnosis of osteoporosis is based on the T-score calculated from bone mineral density (BMD) measurements. BMD measurements have been widely used for the management of osteoporosis, and a low BMD is a strong risk factor for fractures. But BMD measurement has several limitations in both diagnosis, prediction of fracture risk, and treatment follow-up. Quantitative ultrasound (QUS) parameters, an alternative to BMD in the assessment of bone, are independent risk factors for osteoporotic fracture. However, the use of QUS cannot be recommended for both allocation and monitoring of treatment. Biochemical markers of bone remodelling can be useful for both prediction of fracture risk and monitoring of treatment if sources of variability are controlled.     

Difference in bone mass between black and white American children: attributable to body build,sex hormone levels,or bone turnover?

A cross-sectional study of 232 healthy children, with about equal numbers of boys and girls and blacks and whites, aged 4 to 16 yr, was conducted to investigate the racial differences in bone mineral. Bone mineral content (BMC) by dual x-ray absorptiometry was found to be similar between blacks and whites at the spine after controlling for age and Tanner stage. However, total body BMC was higher in blacks, compared with whites of the same age and Tanner stage. Height and weight alone reduced the racial difference in BMC from 152 g to 66 g in girls and from 163 g to 105 g in boys, in whom the difference was further reduced to 66 g after accounting for lean and fat body mass and subscapular skinfold. The only significant sex hormone was androstenedione, which explained another 4-5 g of the racial difference in total body BMC for both boys and girls. Among the biochemical variables, only 25OH vitamin D reduced the residual racial difference in total body BMC to 39 g in girls, whereas serum PTH, urine free deoxypyridinoline ratio, and 1,25(OH)(2) vitamin D reduced the residual difference to 25 g in boys. The residual racial differences in bone mass were not statistically significant.     

Blocking antibody to the β-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis

Low estrogen levels undoubtedly underlie menopausal bone thinning. However, rapid and profuse bone loss begins 3 y before the last menstrual period, when serum estrogen is relatively normal. We have shown that the pituitary hormone FSH, the levels of which are high during late perimenopause, directly stimulates bone resorption by osteoclasts. Here, we generated and characterized a polyclonal antibody to a 13-amino-acid-long peptide sequence within the receptor-binding domain of the FSH β-subunit. We show that the FSH antibody binds FSH specifically and blocks its action on osteoclast formation in vitro. When injected into ovariectomized mice, the FSH antibody attenuates bone loss significantly not only by inhibiting bone resorption, but also by stimulating bone formation, a yet uncharacterized action of FSH that we report herein. Mesenchymal cells isolated from mice treated with the FSH antibody show greater osteoblast precursor colony counts, similarly to mesenchymal cells isolated from FSH receptor (FSHR)(-/-) mice. This suggests that FSH negatively regulates osteoblast number. We confirm that this action is mediated by signaling-efficient FSHRs present on mesenchymal stem cells. Overall, the data prompt the future development of an FSH-blocking agent as a means of uncoupling bone formation and bone resorption to a therapeutic advantage in humans.     

Prospective study of histomorphometry,biochemical bone markers and bone densitometric response to pamidronate in β-thalassaemia presenting with osteopenia-osteoporosis syndrome

This study aimed to evaluate bone remodelling disorders in thalassaemia by using pamidronate (PD) infusion with or without hormone replacement therapy (HRT) as a diagnostic-therapeutic tool. In this prospective study, 24 adult thalassaemia major (TM) and 10 thalassaemia intermedia (TI) patients received either PD and HRT or HRT only (controls) for 3 years. Eugonadal patients with TI had PD only. Bone remodelling was assessed by dual energy X ray absorptiometry (DXA scan), type 1-collagen biochemical bone markers (BBM) and histomorphometry of iliac crest biopsy before and after PD. As a group, thalassaemics had a significant improvement in spinal and femoral bone mineral density Z scores following PD (P < 0·01) compared to the controls. Although BBM were comparable pre-therapy, they were significantly lower in the PD cohort (P < 0·001) compared to the control group. All patients had osteopenia, diminished osteoid formation and bone volume on histomorphometry pre-therapy with high turnover bone disease (HTO) in TM and low-turnover disease (LTO) in TI. In TM, bone volume improved significantly, whereas TI patients showed little or no response to PD. In conclusion, histomorphometry data suggest that TM patients have a distinct pathology of high turnover bone disease compared to TI patients, who have low-turnover disease.     

TGF-β1 signaling and Krüppel-like factor 10 regulate bone marrow-derived proangiogenic cell differentiation, function, and neovascularization

Emerging evidence demonstrates that proangiogenic cells (PACs) originate from the BM and are capable of being recruited to sites of ischemic injury where they contribute to neovascularization. We previously determined that among hematopoietic progenitor stem cells, common myeloid progenitors (CMPs) and granulocyte-macrophage progenitor cells (GMPs) differentiate into PACs and possess robust angiogenic activity under ischemic conditions. Herein, we report that a TGF-β1-responsive Krüppel- like factor, KLF10, is strongly expressed in PACs derived from CMPs and GMPs, ～ 60-fold higher than in progenitors lacking PAC markers. KLF10(-/-) mice present with marked defects in PAC differentiation, function, TGF-β responsiveness, and impaired blood flow recovery after hindlimb ischemia, an effect rescued by wild-type PACs, but not KLF10(-/-) PACs. Overexpression studies revealed that KLF10 could rescue PAC formation from TGF-β1(+/-) CMPs and GMPs. Mechanistically, KLF10 targets the VEGFR2 promoter in PACs which may underlie the observed effects. These findings may be clinically relevant because KLF10 expression was also found to be significantly reduced in PACs from patients with peripheral artery disease. Collectively, these observations identify TGF-β1 signaling and KLF10 as key regulators of functional PACs derived from CMPs and GMPs and may provide a therapeutic target during cardiovascular ischemic states.     

Is there an association between skeletal muscle mass and bone mineral density among African-American, Asian-American, and European-American women?

Skeletal muscle strength is a factor in the growth and maintenance of bone density and both skeletal muscle mass and bone mineral density are related to bone fracture risk. We studied the relationship between total body bone mineral density (TBBMD) and total appendicular skeletal muscle mass (TASM) estimated by dual-energy X-ray absorptiometry (DEXA) in African-American (AA), Asian-American (AsA), and European-American (EA) premenopausal (PRM) and postmenopausal (POM) women. The age- and weight-adjusted TBBMD-TASM association was positive in all PRM race groups and in POM EA, but was negative in POM AA and POM AsA. Body weight and age were positively and negatively associated with TBBMD, respectively, and the relationship was stronger in POM. In all race groups the variability in TBBMD was significantly greater in POM women.     

Incidence,etiology and bone marrow characteristics of non‐chemotherapy‐induced agranulocytosis

Abstract

Objective: Agranulocytosis is a rare but fatal condition. The majority of cases are associated with drugs. However, in‐patient incidences and the relationship between clinical outcomes and bone marrow characteristics have not been established.

Methods: We conducted a retrospective study in a university hospital. A total of 38 in‐patients diagnosed with agranulocytosis were analyzed.

Results: The average incidence of agranulocytosis in Songklanagarind Hospital between 1993 and 2007 was 0·98 cases per 10?000 admissions per year. Antimicrobial agents were the most common etiology (63% of patients) and antithyroid agents were the second most common (13·6%). Two patterns of bone marrow were noted: type I was characterized by a left‐shifted granulopoiesis and type II was recognized as having hypocellular bone marrow with markedly reduced granulocyte precursors. A significantly higher mortality was associated with type II.

Conclusion: Antimicrobial agents are the most common cause and the rare granulocyte precursors in bone marrow are associated with higher mortality rates.     

Effects of 1-year anti-TNF-α therapies on bone mineral density and bone biomarkers in rheumatoid arthritis and ankylosing spondylitis

Clinical Rheumatology - Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have been associated with generalized and localized bone loss. We conducted a comprehensive study using imaging...     

Is a nadir bone marrow required and, if so, what to do with residual disease?

Current National Comprehensive Cancer Network guidelines for acute myeloid leukemia (AML) treatment state that bone marrow biopsies should be completed 7-10 days after completion of chemotherapy. Treatment decisions change based on cellularity of that biopsy. Several studies show that bone marrow aspirates at nadir can be used to predict complete remission (CR) and overall survival. Many groups have attempted to modify induction regimens based on results of bone marrow biopsies with mixed results. This paper will review the current literature on using bone marrow biopsy to prognosticate and guide treatment for AML patients.     

Effect of interleukin-3, stem cell factor and granulocyte–macrophage colony-stimulating factor on committed stem cells, long-term culture initiating cells and bone marrow stroma in a one-step long-term bone marrow culture

Received: May 26, 1999 / Accepted: October 8, 1999     

A case of Marinesco-Sjögren syndrome: MRI observations of skeletal muscles, bone metabolism, and treatment with testosterone and risedronate

Marinesco-Sj?gren syndrome (MSS) is a rare autosomal recessive disorder characterized by cerebellar ataxia, congenital cataracts, mental retardation, primary hypogonadism, skeletal abnormalities and myopathy, and patients with MSS are considered to be at risk of falls and bone fractures. We report a patient with MSS who received testosterone replacement therapy and risedronate administration. Muscle strength and the MRI features of the skeletal muscles were not changed, but low bone mass was improved by these treatments, and improvement has continued after risedronate treatment alone. This case suggests that treatment of MSS-related low bone mass using bisphosphonates is likely beneficial.