High Bone Turnover Osteoporosis Research Articles

Comparison of the Efficacy and Renal Safety of Bisphosphonate Between Low-Dose/High-Frequency and High-Dose/Low-Frequency Regimens in a Late-Stage Chronic Kidney Disease Rat Model.

The efficacy and renal safety of low-dose/high-frequency (LDHF) dosing and high-dose/low-frequency (HDLF) dosing of bisphosphonates (BPs) are comparable in patients with normal kidney function but might be different in patients with late-stage chronic kidney disease (CKD). This study aimed to compare the efficacy and renal safety of two different dosage regimens of a BP, alendronate (ALN), in stage 4 CKD using a rat model. Male, 10-week-old Sprague-Dawley rats were subjected to either 5/6 nephrectomy or sham surgery. The animals received subcutaneous administration of vehicle (daily) or ALN in LDHF dosage regimen (LDHF-ALN: 0.05mg/kg/day) or HDLF dosage regimen (HDLF-ALN: 0.70mg/kg/2weeks). Medications commenced at 20weeks of age and continued for 10weeks. Micro-computed tomography, histological analysis, infrared spectroscopic imaging, and serum and urine assays were performed to examine the efficacy and renal safety of the ALN regimens. Both LDHF-ALN and HDLF-ALN increased bone mass, improved micro-structure, and enhanced mechanical properties, without causing further renal impairment in CKD rats. Histologically, however, HDLF-ALN more efficiently suppressed bone turnover, leading to more mineralized trabecular bone, than LDHF-ALN in CKD rats, whereas such differences between LDHF-ALN and HDLF-ALN were not observed in sham rats. Both LDHF-ALN and HDLF-ALN showed therapeutic effects on high bone turnover osteoporosis in CKD stage 4 rats without causing further renal impairment. However, as HDLF-ALN more efficiently suppressed bone turnover than LDHF-ALN in late-stage CKD, HDLF-ALN might be more appropriate than LDHF-ALN for fracture prevention in high bone turnover osteoporosis patients with late-stage CKD.

Thyroid Hormone Diseases and Osteoporosis.

Thyroid hormones are essential for normal skeletal development and normal bone metabolism in adults but can have detrimental effects on bone structures in states of thyroid dysfunction. Untreated severe hyperthyroidism influences the degree of bone mass and increases the probability of high bone turnover osteoporosis. Subclinical hyperthyroidism, defined as low thyrotropin (TSH) and free hormones within the reference range, is a subtler disease, often asymptomatic, and the diagnosis is incidentally made during screening exams. However, more recent data suggest that this clinical condition may affect bone metabolism resulting in decreased bone mineral density (BMD) and increased risk of fracture, particularly in postmenopausal women. The main causes of exogenous subclinical hyperthyroidism are inappropriate replacement dose of thyroxin and TSH suppressive L-thyroxine doses in the therapy of benign thyroid nodules and thyroid carcinoma. Available data similarly suggest that a long-term TSH suppressive dose of thyroxin may decrease BMD and may induce an increased risk of fracture. These effects are particularly observed in postmenopausal women but are less evident in premenopausal women. Overt hypothyroidism is known to lower bone turnover by reducing both osteoclastic bone resorption and osteoblastic activity. These changes in bone metabolism would result in an increase in bone mineralization. At the moment, there are no clear data that demonstrate any relationship between BMD in adults and hypothyroidism. Despite these clinical evidences, the cellular and molecular actions of thyroid hormones on bone structures are not complete clear.

The androgen receptor is required for maintenance of bone mass in adult male mice

Previous studies evaluating the role of the androgen receptor (AR) for bone mass have used mouse models with global or tissue-specific lifelong inactivation of the AR. However, these mouse models have the AR inactivated already early in life and the relative roles of the AR during development, sexual maturation and in adult mice cannot be evaluated separately. The aim of the present study was to determine the specific roles of the AR in bone during sexual maturation and in adult mice. The AR was conditionally ablated at four (pre-pubertal) or ten (post-pubertal) weeks of age in male mice using tamoxifen-inducible Cre-mediated recombination. Both the pre-pubertal and the post-pubertal AR inactivation were efficient demonstrated by substantially lower AR mRNA levels in seminal vesicle, bone and white adipose tissue as well as markedly reduced weights of reproductive tissues when comparing inducible ARKO mice and control mice at 14 weeks of age. Total body BMD, as analyzed by DXA, as well as tibia diaphyseal cortical bone thickness and proximal metaphyseal trabecular bone volume fraction, as analyzed by μCT, were significantly reduced by both pre-pubertal and post-pubertal AR inactivation. These bone effects were associated with an increased bone turnover, indicating a high bone turnover osteoporosis. Pre-pubertal but not post-pubertal AR inactivation resulted in substantially increased fat mass. In conclusion, the AR is required for maintenance of both trabecular and cortical bone in adult male mice while AR expression during puberty is crucial for normal fat mass homeostasis in adult male mice.

Type 1 diabetes mellitus induced low bone turnover in ovariectomized rats.

To investigate type 1 diabetes mellitus (T1DM) affecting bone remodeling in the context of menopause in female rats. The animals were subjected to either ovariectomy (OVX) which was performed to mimic postmenopausal estrogen deficiency, and/or type 1 diabetes mellitus which was established by the intra-abdominal administration of 50 mg/kg streptozotocin (STZ). Single-loaded groups were the OVX group and the STZ group, while the combined group was the OVX+STZ group. Bone histomorphometry was performed on the tibial metaphysis by Micro-CT scanning. Immunohistochemistry was used to assess the activity of osteoblast and osteoclast by counteracting with antibodies against their respective specific marker enzymes. The gene expression of key molecules involved in osteoblastic and osteoclastic signaling pathways were analyzed by RT-qPCR. The results showed a significant bone volume decrease in both single-loaded groups and combined group with the combined group suffering greatest bone loss and bone structural deterioration (p<0.001). Immunohistochemical staining and RT-qPCR revealed an increase in osteoblastic (p<0.001) and osteoclastic (p<0.01) activities in OVX rats while there was a decrease (p<0.05) in those of STZ rats. When OVX and STZ were combined, the rats exhibited a further decrease in osteoblastic activity (p<0.001) and a similar level of osteoclastic activity (p>0.05) compared to their STZ counterparts. These results demonstrated that STZ-induced T1DM reverses OVX-associated high bone turnover osteoporosis to the type of low bone turnover, leading to greater bone loss and structural defect.

Effect of prednisone treatment for 30 and 90days on bone metabolism in collagen-induced arthritis (CIA) rats.

Glucocorticoids (GCs) are often prescribed to treat rheumatoid arthritis (RA) in the long term, but there is still controversy in the administration of GCs, mainly because of the adverse reactions such as osteoporosis. Numerous studies have demonstrated that osteoporosis could be induced by GCs in normal rats. However, few experiments have focused on whether osteoporosis could be induced or aggravated by GCs in collagen induced arthritis (CIA) rats. We have investigated bone changes in CIA rats treated with prednisone at 4.5mg/kg/day for 30 and 90days by bone histomorphometry, bone mineral density (BMD), micro-CT, biomechanical test, and enzyme-linked immunosorbant assay. We found that high bone turnover osteoporosis was shown in CIA rats. Prednisone treatment for 30 and 90days improved articular structure and decelerated the degeneration of the femur in CIA rats, but did not improve BMD and bone biomechanics. We conclude that osteoporosis was not aggravated in CIA rats treated with prednisone for 30 and 90days. On the contrary, prednisone treatment for 30 and 90days could prevent bone loss of the femur in CIA rats. There was a negative effect on bone metabolism in CIA rats treated with prednisone for 90days.

Urinary calcium excretion and bone turnover in osteoporotic patients

It is well documented that patients with osteoporosis (OP) have high incidence of hypercalciuria (HC). However, the mechanism of HC in patients with OP is not well established. It is thought to be the result of high bone turnover (HBT) with excessive bone resorption. OP also frequently presents with low bone turnover (LBT). At this time, it is not clear whether OP with LBT is also associated with hypercalciuria. The purpose of this study is to evaluate urinary calcium excretion in osteoporotic patients with HBT and LBT. This is a retrospective study of 132 patients with osteoporosis who underwent bone biopsy at the University of Kentucky between January 2010 and December 2012. Based on bone biopsy results, patients were divided into HBT or LBT groups. Demographic data, medical history, bone mineral density, serum creatinine, calcium, phosphorus, estimated glomerular filtration rate (eGFR), filtered calcium load, fractional excretion of calcium and phosphorus, 25-hydroxy vitamin D levels, and 24-hour urinary calcium excretion and creatinine were obtained from the patients' medical records. Also, intact parathyroid hormone (iPTH), serum osteocalcin, bone-specific alkaline phosphatase, N-telopeptide of type I collagen, and urine pyridinium levels were measured. Hypercalciuria was present in approximately half of the patients in both the HBT and LBT groups. Patients with HBT OP were significantly younger than those with LBT OP (p=0.013). There was no difference between HBT and LBT patients in 24-hour urinary calcium excretion, serum creatinine, calcium, phosphorus, eGFR, filtered calcium load, and fractional excretion of phosphorus. Mean values of serum osteocalcin and serum N-telopeptide of type I collagen were significantly lower in the LBT compared to the HBT group (p=0.000 and 0.0152, respectively). There was a significant correlation between filtered calcium load and urinary calcium excretion in HBT patients but not in patients with LBT. Fractional excretion of calcium significantly correlated with urinary calcium excretion in both groups. There was no correlation between kidney function and 24-hour urinary calcium excretion. There was no correlation between dual-emission X-ray absorptiometry T-scores and 24-hour urinary calcium excretion. HC is frequently present in patients with OP regardless of the underlying bone turnover status. This may suggest the presence of a bone-derived renal calcium regulating factor(s). Further studies are needed to understand the exact mechanism and the potential consequences of HC in OP patients. .

Long-term safety of antiresorptive treatment: bone material, matrix and mineralization aspects.

It is well established that long-term antiresorptive use is effective in the reduction of fracture risk in high bone turnover osteoporosis. Nevertheless, during recent years, concerns emerged that longer bone turnover reduction might favor the occurrence of fatigue fractures. However, the underlying mechanisms for both beneficial and suspected adverse effects are not fully understood yet. There is some evidence that their effects on the bone material characteristics have an important role. In principle, the composition and nanostructure of bone material, for example, collagen cross-links and mineral content and crystallinity, is highly dependent on tissue age. Bone turnover determines the age distribution of the bone structural units (BSUs) present in bone, which in turn is decisive for its intrinsic material properties. It is noteworthy that the effects of bone turnover reduction on bone material were observed to be dependent on the duration of the antiresorptive therapy. During the first 2-3 years, significant decreases in the heterogeneity of material properties such as mineralization of the BSUs have been observed. In the long term (5-10 years), the mineralization pattern reverts towards normal heterogeneity and degree of mineralization, with no signs of hypermineralization in the bone matrix. Nevertheless, it has been hypothesized that the occurrence of fatigue fractures (such as atypical femoral fractures) might be linked to a reduced ability of microdamage repair under antiresorptive therapy. The present article examines results from clinical studies after antiresorptive, in particular long-term, therapy with the aforementioned potentially positive or negative effects on bone material.

THU0079 Anti-IL-6 Receptor Antibody Suppresses Systemic Bone Loss by not Only Normalizing Bone Resorption but also Enhancing Bone Formation in a Mouse Model of Collagen-Induced Arthritis

BackgroundPatients with rheumatoid arthritis (RA) have a high risk of osteoporosis and osteoporotic fracture. In primary osteoporosis (either high bone turnover osteoporosis [type I] or low bone turnover osteoporosis [type...

The skeletal consequences of thyrotoxicosis

Euthyroid status is essential for normal skeletal development and the maintenance of adult bone structure and strength. Established thyrotoxicosis has long been recognised as a cause of high bone turnover osteoporosis and fracture but more recent studies have suggested that subclinical hyperthyroidism and long-term suppressive doses of thyroxine (T4) may also result in decreased bone mineral density (BMD) and an increased risk of fragility fracture, particularly in postmenopausal women. Furthermore, large population studies of euthyroid individuals have demonstrated that a hypothalamic-pituitary-thyroid axis set point at the upper end of the normal reference range is associated with reduced BMD and increased fracture susceptibility. Despite these findings, the cellular and molecular mechanisms of thyroid hormone action in bone remain controversial and incompletely understood. In this review, we discuss the role of thyroid hormones in bone and the skeletal consequences of hyperthyroidism.

Fragility Fractures in Men with Idiopathic Osteoporosis Are Associated with Undermineralization of the Bone Matrix without Evidence of Increased Bone Turnover

The pathogenesis of primary osteoporosis in younger individuals is still elusive. An important determinant of the biomechanical competence of bone is its material quality. In this retrospective study we evaluated bone material quality based on quantitative backscattered electron imaging to assess bone mineralization density distribution (BMDD) in bone biopsies of 25 male patients (aged 18-61 years) who sustained fragility fractures but were otherwise healthy. BMDD of cancellous bone was compared with previously established adult reference data. Complementary information was obtained by bone histomorphometry. The histomorphometric results showed a paucity of osteoblasts and osteoclasts on the bone surface in the majority of patients. BMDD revealed a significant shift to lower mineralization densities for cancellous bone values: CaMean (weighted mean Ca content, -5.9%), CaPeak (mode of the BMDD, -5.6%), and CaHigh (portion of fully mineralized bone, -76.8%) were decreased compared to normative reference; CaWidth (heterogeneity in mineralization, +18.5%) and CaLow (portion of low mineralized bone, +68.8; all P < 0.001) were significantly increased. The shift toward lower mineral content in the bone matrix in combination with reduced indices of bone formation and bone resorption suggests an inherent mineralization defect leading to undermineralized bone matrix, which might contribute to the susceptibility to fragility fractures of the patients. The alteration in bone material might be related to osteoblastic dysfunction and seems fundamentally different from that in high bone turnover osteoporosis with a negative bone balance.

Osteoporosis in MCHR1-deficient mice

It is well recognized that the hypothalamus is of central importance in the regulation of food intake and fat mass. Recent studies indicate that it also plays an important role in the regulation of bone mass. Melanin concentrating hormone (MCH) is highly expressed in the hypothalamus and has been implicated in regulation of energy homeostasis. We developed MCHR1 inactivated mice to evaluate the physiological role of this receptor. Interestingly, the MCHR1 −/− mice have osteoporosis, caused by a reduction in the cortical bone mass, while the amount of trabecular bone is unaffected. The reduction in cortical bone mass is due to decreased cortical thickness. Serum levels of c-telopeptide, a marker of bone resorption, are increased in MCHR1 −/− mice, indicating that the MCHR1 −/− mice have a high bone turnover osteoporosis. In conclusion, the MCHR1 −/− mice have osteoporosis, indicating that MCHR1-signalling is involved in a tonic stimulation of bone mass.