Incidence and bone biopsy findings of atypical femoral fractures

Authors

Inari S. Tamminen, Tero Yli-Kyyny, Hanna Isaksson, Mikael J. Turunen, Xiaoyu Tong, Jukka S. Jurvelin, Heikki Kröger

Abstract

Bisphosphonates are widely used in the treatment of osteoporosis. It has been suggested that bisphosphonate treatment may be associated with atypical femoral fractures (AFFs), severely suppressed bone turnover rate, and decreased mineralization. We studied bone properties using bone quantitative histomorphometry and Fourier transform infrared spectroscopic imaging (FTIRI) on patients with AFFs. Further, the incidence of AFFs was estimated. Patient records of Kuopio University Hospital, Finland from January 2007 to June 2009 were reviewed to identify all patients who had sustained and had been operated for AFF (n = 8). The incidence of AFFs among patients on bisphosphonates was 0.61 fractures/1,000 patients per year, compared to 0.0067/1,000 per year among untreated patients. The patients that underwent bone biopsy (n = 4) were postmenopausal women (aged 55.5–81.1 years) who had been treated with bisphosphonates for over 4 years. Histomorphometry revealed low trabecular bone volume. Bone formation and resorption parameters tended to be low. Trabecular bone single labels were detected in one patient in the region of interest. In the extended label search, trabecular bone double labels were found in two patients. Based on FTIRI results, higher phosphate-to-amide I ratio and collagen maturity were found compared to normal samples. The heterogeneity of phosphate-to-amide I ratio was low. Overall incidence of atypical femoral fractures is low. The poor fracture resistance in some patients on long-term bisphosphonate-therapy could be explained by low bone formation, and changes in bone composition, i.e., higher degree of mineralization, increased collagen maturity, and decreased heterogeneity of the degree of mineralization.

Link to Article

http://dx.doi.org/10.1007/s00774-013-0448-7

A peptidomimetic antagonist of the alpha(v)beta3 integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo

Authors

V W Engleman, G A Nickols, F P Ross, M A Horton, D W Griggs, S L Settle, P G Ruminski and S L Teitelbaum

Abstract

Osteoclastic bone degradation requires intimacy between the matrix and the resorptive cell. While the precise role the integrin alpha(v)beta3 plays in the process is not yet understood, occupancy of the heterodimer by soluble ligand or by blocking antibody effectively inhibits bone resorption in vitro and in vivo, suggesting that alpha(v)beta3 blockade may prevent postmenopausal osteoporosis. Thus, we identified a synthetic chemical peptide mimetic, beta-[2-[[5-[(aminoiminomethyl)amino]-1-oxopentyl]amino]-1-+ ++oxoethyl]amino-3-pyridinepropanoic acid, bistrifluoroacetate (SC56631) based upon the alpha(v)beta3 ligand, Arg-Gly-Asp (RGD), which recognizes the isolated integrin, and its relative, alpha(v)beta5, as effectively as does the natural peptide. The mimetic dampens osteoclastic bone resorption in vitro and in vivo. Most importantly, intravenous administration of the mimetic prevents the 55% loss of trabecular bone sustained by rats within 6 wk of oophorectomy. Histological examination of bones taken from SC56631-treated, oophorectomized animals also demonstrates the compound's bone sparing properties and its capacity to decrease osteoclast number. Thus, an RGD mimetic prevents the rapid bone loss that accompanies estrogen withdrawal.

Link to Article

http://dx.doi.org/10.1172/JCI119404

Prolonged alendronate treatment prevents the decline in serum TGF-β1 levels and reduces cortical bone strength in long-term estrogen deficiency rat model

Authors

Junjing Jia, Wei Yao, Sarah Amugongo, Mohammad Shahnazari, Weiwei Dai, Yu-An E. Lay, Diana Olvera, Elizabeth A. Zimmermann, Robert O. Ritchie, Chin-Shang Li, Tamara Alliston, Nancy E. Lane

Abstract

While the anti-resorptive effects of the bisphosphonates (BPs) are well documented, many questions remain about their mechanisms of action, particularly following long-term use. This study evaluated the effects of alendronate (Ale) treatment on TGF-β1 signaling in mesenchymal stem cells (MSCs) and osteocytes, and the relationship between prolonged alendronate treatment on systemic TGF-β1 levels and bone strength. TGF-β1 expression and signaling were evaluated in MSCs and osteocytic MLO-Y4 cells following Ale treatment. Serum total TGF-β1 levels, a bone resorption marker (DPD/Cr), three-dimensional microCT scans and biomechanical tests from both the trabecular and cortical bone were measured in ovariectomized rats that either received continuous Ale treatment for 360days or Ale treatment for 120days followed by 240days of vehicle. Linear regression tests were performed to determine the association of serum total TGF-β1 levels and both the trabecular (vertebrae) and cortical (tibiae) bone strength. Ale increased TGF-β1 signaling in the MSCs but not in the MLO-Y4 cells. Ale treatment increased serum TGF-β1 levels and the numbers of TGF-β1-positive osteocytes and periosteal cells in cortical bone. Serum TGF-β1 levels were not associated with vertebral maximum load and strength but was negatively associated with cortical bone maximum load and ultimate strength. The increase of serum TGF-β1 levels during acute phase of estrogen deficiency is likely due to increased osteoclast-mediated release of matrix-derived latent TGF-β1. Long-term estrogen-deficiency generally results in a decline in serum TGF-β1 levels that are maintained by Ale treatment. Measuring serum total TGF-β1 levels may help to determine cortical bone quality following alendronate treatment.

Link to Article

http://dx.doi.org/10.1016/j.bone.2012.10.017

Histone deacetylase 3 is required for maintenance of bone mass during aging

Authors

Meghan E. McGee-Lawrence, Elizabeth W. Bradley, Amel Dudakovic, Samuel W. Carlson, Zachary C. Ryan, Rajiv Kumar, Mahrokh Dadsetan, Michael J. Yaszemski, Qingshan Chen, Kai-Nan An, Jennifer J. Westendorf

Abstract

Histone deacetylase 3 (Hdac3) is a nuclear enzyme that removes acetyl groups from lysine residues in histones and other proteins to epigenetically regulate gene expression. Hdac3 interacts with bone-related transcription factors and co-factors such as Runx2 and Zfp521, and thus is poised to play a key role in the skeletal system. To understand the role of Hdac3 in osteoblasts and osteocytes, Hdac3 conditional knockout (CKO) mice were created with the osteocalcin (OCN) promoter driving Cre expression. Hdac3 CKOOCN mice were of normal size and weight, but progressively lost trabecular and cortical bone mass with age. The Hdac3 CKOOCN mice exhibited reduced cortical bone mineralization and material properties and suffered frequent fractures. Bone resorption was lower, not higher, in the Hdac3 CKOOCN mice, suggesting that primary defects in osteoblasts caused the reduced bone mass. Indeed, reductions in bone formation were observed. Osteoblasts and osteocytes from Hdac3 CKOOCN mice showed increased DNA damage and reduced functional activity in vivo and in vitro. Thus, Hdac3 expression in osteoblasts and osteocytes is essential for bone maintenance during aging.

Link to Article

http://dx.doi.org/10.1016/j.bone.2012.10.015

Soy protein with or without isoflavones failed to preserve bone density in gonadal hormone–deficient male rat model of osteoporosis

Authors

Shanil S. Juma, Zahra Ezzat-Zadeh, Dania A. Khalil, Shirin Hooshmand, Mohammed Akhter, Bahram H. Arjmandi

Abstract

Soy with its isoflavones has been shown to positively influence bone mineral density in female ovariectomized rats; hence, we hypothesized a similar effect in orchidectomized (ORX) male rats. Forty male Sprague-Dawley rats, aged 95 days, were divided into 4 groups and were either sham operated (Sham) or ORX. The ORX groups were fed a soy protein–based diet (SOY), an isoflavone-depleted soy protein diet (SOY−), or a casein based diet for 65 days after surgery. Orchidectomy increased the rate of bone turnover, resulting in reduced bone mineral density and bone mineral content by 3.5% and 14%, respectively, and compromised biomechanical properties. The mean femoral length of ORX animals was also significantly shorter than Sham animals, but ORX rats that were fed SOY diet did not experience this reduction in bone length, implicating a role for soy protein in bone growth (4.02 ± 0.02, 3.93 ± 0.01, 3.99 ± 0.02, 3.91 ± 0.01 for Sham, ORX, SOY, SOY−, respectively). The SOY and SOY− positively influenced the biomechanical properties of bone such as yield and ultimate force, the measures of bone elasticity, and plasticity. In terms of bone histomorphometry, the data indicate that SOY− tends to reduce ORX-induced increase in bone turnover as evidenced by suppressed bone formation rate/mineralized surface by about 9%. Overall, our results indicated that soy protein, regardless of its isoflavone content, was unable to prevent the ORX-induced femoral decrease in bone density and mineral content. However, soy may enhance the quality of bone as indicated by increased yield force.

Link to Article

http://dx.doi.org/10.1016/j.nutres.2012.08.001

Hyperthyroid-associated osteoporosis is exacerbated by the loss of TSH signaling

Authors

Ramkumarie Baliram, Li Sun, Jay Cao, Jianhua Li, Rauf Latif, Amanda K. Huber, Tony Yuen, Harry C. Blair, Mone Zaidi, and Terry F. Davies

Abstract

The osteoporosis associated with human hyperthyroidism has traditionally been attributed to elevated thyroid hormone levels. There is evidence, however, that thyroid-stimulating hormone (TSH), which is low in most hyperthyroid states, directly affects the skeleton. Importantly, Tshr-knockout mice are osteopenic. In order to determine whether low TSH levels contribute to bone loss in hyperthyroidism, we compared the skeletal phenotypes of wild-type and Tshr-knockout mice that were rendered hyperthyroid. We found that hyperthyroid mice lacking TSHR had greater bone loss and resorption than hyperthyroid wild-type mice, thereby demonstrating that the absence of TSH signaling contributes to bone loss. Further, we identified a TSH-like factor that may confer osteoprotection. These studies suggest that therapeutic suppression of TSH to very low levels may contribute to bone loss in people.

Link to Article

http://dx.doi.org/10.1172/JCI63948