No abstract

Bisphosphonates are the most widely prescribed pharmacologic treatment for osteoporosis and reduce fracture risk in postmenopausal women by up to 50%. However, in the past decade these drugs have been associated with atypical femoral fractures (AFFs), rare fractures with a transverse, brittle morphology. The unusual fracture morphology suggests that bisphosphonate treatment may impair toughening mechanisms in cortical bone. The objective of this study was to compare the compositional and mechanical properties of bone biopsies from bisphosphonate-treated patients with AFFs to those from patients with typical osteoporotic fractures with and without bisphosphonate treatment. Biopsies of proximal femoral cortical bone adjacent to the fracture site were obtained from postmenopausal women during fracture repair surgery (fracture groups, n = 33) or total hip arthroplasty (nonfracture groups, n = 17). Patients were allocated to five groups based on fracture morphology and history of bisphosphonate treatment [+BIS Atypical: n = 12, BIS duration: 8.2 (3.0) y; +BIS Typical: n = 10, 7.7 (5.0) y; +BIS Nonfx: n = 5, 6.4 (3.5) y; −BIS Typical: n = 11; −BIS Nonfx: n = 12]. Vibrational spectroscopy and nanoindentation showed that tissue from bisphosphonate-treated women with atypical fractures was harder and more mineralized than that from bisphosphonatetreated women with typical osteoporotic fractures. In addition, fracture mechanics measurements showed that tissue from patients treated with bisphosphonates had deficits in fracture toughness, with lower crack-initiation toughness and less crack deflection at osteonal boundaries than that of bisphosphonate-naïve patients. Together, these results suggest a deficit in intrinsic and extrinsic toughening mechanisms, which contribute to AFFs in patients treated with long-term bisphosphonates.atypical fracture | bisphosphonates | subtrochanteric fracture | fracture toughness | FTIR imaging

Background-Tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) are thought to play critical roles in vascular remodeling after injury, with tPA mediating intravascular clot lysis and uPA modulating cell migration within the vessel wall. In human vascular disease, however, thrombus organization and neointimal formation are closely interrelated processes. This study examines the differential roles of tPA and uPA in these processes in mice. Methods and Results-Carotid artery injury and thrombosis were induced in wild-type (WT), uPA-deficient (uPA Ϫ/Ϫ ), and tPA-deficient (tPA Ϫ/Ϫ ) mice with the use of ferric chloride. The expression of uPA and tPA was significantly upregulated in the vessel wall of WT mice 1 week after injury, and compared with WT mice, uPA Ϫ/Ϫ and tPA Ϫ/Ϫ mice had lower carotid patency rates after injury. At 3 weeks, only 55% of uPA Ϫ/Ϫ mouse vessels were patent compared with 81% in tPA Ϫ/Ϫ mice and 100% in WT mice (Pϭ0.014). Morphometric analysis of injured arterial segments revealed severe luminal stenosis (62Ϯ28%) in uPA Ϫ/Ϫ mice compared with their tPA Ϫ/Ϫ (16Ϯ12%) and WT (6.3Ϯ3.6%, PϽ0.001) counterparts. Moreover, although the vascular walls of WT mice and, particularly, tPA Ϫ/Ϫ mice developed a cell-rich multilayered neointima and media, the lumen of uPA Ϫ/Ϫ vessels remained obstructed with acellular unorganized thrombotic material, and their medial areas did not expand. Conclusions-These results indicate that the roles of uPA and tPA in the arterial response to injury are different and more complex than previously assumed and emphasize the critical role of thrombus organization and resolution in neointimal formation and vascular pathology.

Within the mineralized bone, osteocytes form a multifunctional mechanosensitive network orchestrating bone remodelling. A preserved osteocyte population is a crucial determinant of bone quality. In human auditory ossicles, the early decrease in osteocyte numbers but maintained integrity remains an unexplained phenomenon that might serve for sound transmission from air to the labyrinth. Here we analysed the frequency, size and composition of osteocyte lacunae in the auditory ossicles of 22 individuals from early postnatal period to old age. Mineralization of the bone matrix was determined using backscattered electron imaging. No signs of bone remodelling were observed above the age of 1 year. We detected characteristics of early bone tissue aging, such as decrease in osteocytes, lower total lacunar density and lacunar area, as well as high matrix mineralization accompanied by distinct accumulation of micropetrotic lacunae and decreased indentation depths. The majority of these changes took place in the first months and years of life, while afterwards only minor reorganization was present. With osteocyte apoptosis potentially being a consequence of low mechanical stimuli, the early loss of osteocytes without initiation of bone remodelling indicates an adaptive response conserving the architecture of the auditory ossicles and ensuring stable sound transmission throughout life.The human auditory ossicles malleus, incus and stapes present with their final morphology at birth, while in later life decades only minor morphological changes occur 1 . The ossicles are located in the air-filled middle ear and serve for transmission of sound-induced mechanical vibrations from the eardrum to the oval window of the fluid-filled cochlea 2 . Damage or deformation of the ossicular chain lead to conductive hearing loss 3 . While malleus and incus develop from the first pharyngeal arch, the stapes which is the smallest bone in the human body has two embryologically distinct parts. In fact, the cranial end of the second pharyngeal arch forms an independent anlage, which develops into a superior and an inferior part. The superior part gives origin to the base of the stapes, whereas the inferior part forms the limbs (anterior and posterior crus) and the head of the stapes 4 . As sound transmission is the major function of the auditory ossicles and biomechanical loads are minor 5 , adaptive bone remodelling might be unnecessary here. In general, the absence of bone remodelling as seen with aging would be associated with hypermineralization of the bone matrix itself, but also with the accumulation of hypermineralized (micropetrotic) osteocyte lacunae 6,7 . The latter describes the in vivo formation of intra-lacunar calcification 8 , which is believed to follow apoptosis of some osteocytes 7 . Hypermineralized osteocyte lacunae accumulate in aged 6 , osteoporotic 9 and osteoarthritic 10 bone. In the ossicles, increased numbers of dead osteocytes as a sign of impaired bone remodelling have been reported 11,12 , however the degree of miner...