Yoon Taek Kim

The nerve endings of the acetabular labrum.

The nerve endings of the human acetabular labrum were investigated. Twenty-three acetabular labra were obtained from 24 fresh human cadavers, stained with Suzukis silver impregnation and an immunohistochemical technique for neurogenic specific protein S-100, and examined by light and electron microscopy. Ramified free nerve endings were seen in all specimens by silver staining, and also were observed by the immunohistochemical technique for S-100 protein. Sensory nerve end organs, such as a Vater-Pacini corpuscle, Golgi-Mazzoni corpuscle, Ruffini corpuscle, and articular corpuscle (Krause corpuscle), were observed by silver staining. Collagen fibers were scattered sparsely in the superficial layer of the labrum, and nerve endings were observed mostly in this region. Collagen fibers were sparse, and nerve endings also were observed in some regions among the collagen fiber bundles in the inner layer. Innervation of the acetabular labrum was confirmed in this study, suggesting that nerve endings in the labrum may be involved in nociceptive and proprioceptive mechanisms.

Aberrant histone acetylation contributes to elevated interleukin-6 production in rheumatoid arthritis synovial fibroblasts.

Accumulating evidence indicates that epigenetic aberrations have a role in the pathogenesis of rheumatoid arthritis (RA). However, reports on histone modifications are as yet quite limited in RA. Interleukin (IL)-6 is an inflammatory cytokine which is known to be involved in the pathogenesis of RA. Here we report the role of histone modifications in elevated IL-6 production in RA synovial fibroblasts (SFs). The level of histone H3 acetylation (H3ac) in the IL-6 promoter was significantly higher in RASFs than osteoarthritis (OA) SFs. This suggests that chromatin structure is in an open or loose state in the IL-6 promoter in RASFs. Furthermore, curcumin, a histone acetyltransferase (HAT) inhibitor, significantly reduced the level of H3ac in the IL-6 promoter, as well as IL-6 mRNA expression and IL-6 protein secretion by RASFs. Taken together, it is suggested that hyperacetylation of histone H3 in the IL-6 promoter induces the increase in IL-6 production by RASFs and thereby participates in the pathogenesis of RA.

Clinical and radiographic outcomes of total hip replacement with poly(2-methacryloyloxyethyl phosphorylcholine)-grafted highly cross-linked polyethylene liners: Three-year results of a prospective consecutive series

Abstract Objectives. This study aimed to evaluate the clinical safety and wear-resistance of the novel highly cross-linked polyethylene (HXLPE) acetabular liner with surface grafting of poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) at 3 years after total hip replacement (THR). Methods. Eighty consecutive patients underwent cementless THR using a 26-mm diameter cobalt–chromium–molybdenum alloy femoral head and a PMPC-grafted HXLPE liner for the bearing couplings. We evaluated the clinical and radiographic outcomes of 76 patients at 3 years after the index surgery. Results. The clinical results at 3 years were equivalent to a Harris hip score of 95.6 points. No adverse events were associated with the implanted PMPC-grafted HXLPE liner, and no periprosthetic osteolysis was detected. The mean femoral head penetration rate was 0.002 mm/year, representing marked reduction compared with other HXLPE liners. Conclusions. A PMPC-grafted HXLPE liner is a safe option in THR and probably reduces the generation of wear particles.

Improvement of skeletal fragility by teriparatide in adult osteoporosis patients: a novel mechanostat-based hypothesis for bone quality.

SKELETAL ADAPTATION TO MECHANICAL STRAIN IN HUMANS Several lines of clinical evidence (1–3) suggest that the adult skeleton in humans continuously responds to change in mechanical environment to maintain resultant “elastic” deformation (strain) of bone; increased or decreased bone strain would normally induce bone gain or loss, respectively. Indeed, skeletal adaptation to mechanical strain, known as the mechanostat (4–6), plays a significant role in the treatment of osteoporosis. For example, bone strain from habitual physical activity decreases when an osteoporosis drug increases bone strength, indicating that the effect of osteoporosis therapy is limited by mechanical strain-related feedback control; this mechanostat-based logic is consistent with various clinical data (3). Approaches to reduce the limitation of osteoporosis therapy include pharmacologically enhancing skeletal response to mechanical loading, and earlier experimental studies using external mechanical loading models show that intermittent treatment with parathyroid hormone has such a possibility (7, 8). Importantly, treatment with teriparatide could synergistically produce bone gain with even low, physiological levels of mechanical loading in humans (9) as well as animals (10). The present article concisely discusses the effects of daily or weekly treatment with teriparatide and proposes a new mechanostat-based hypothesis for bone quality associated with mineral versus collagen. DAILY OR WEEKLY TREATMENT WITH TERIPARATIDE IN OSTEOPOROSIS In Japan, not only daily subcutaneous injection of teriparatide (20 μg/day) (11– 13) but also weekly subcutaneous injection of teriparatide (56.5 μg/week) (14, 15) has been approved for the treatment of adult osteoporosis patients with high risk of fracture. Interestingly, there are marked differences in the effects of these two treatments on circulating markers of bone formation and resorption. The daily injection results in a rapid and sustained increase in bone formation markers followed by a delayed increase in bone resorption markers (12); the period of time during which the increase in bone formation is superior to that in bone resorption is called the anabolic window (16). In contrast, the weekly injection induces only a transient increase in bone formation markers without an increase in bone resorption markers (14). Formation and resorption occur on different surfaces during bone modeling, and thus modeling-based bone formation and resorption are not coupled; such uncoupling factors include mechanical loading that stimulates bone formation and suppresses bone resorption. Modeling-based bone formation by histomorphometry (17, 18) as well as an increase in bone formation markers and a decrease in bone resorption markers in blood (19) are observed during the first month of daily treatment with teriparatide, which is consistent with clinical finding suggesting that daily treatment with teriparatide and normal physical activity synergistically produce bone gain (9). A rapid but transient increase in bone formation markers without an increase in bone resorption markers (14) implies that weekly treatment with teriparatide also stimulates modeling-based bone formation. On the other hand, long-term daily, but not weekly, treatment with teriparatide causes increases in both bone formation and resorption markers (12, 14). These systemic changes agree with histomorphometric data showing that 1 or 2 years of daily treatment with teriparatide results in an increase in remodeling-based bone formation (20); resorption followed by formation occurs on the same surface during bone remodeling and thus remodelingbased bone resorption and formation are coupled. Increased or decreased bone remodeling lowers or raises, respectively, the degree of mineralization (21), and cortical volumetric bone mineral density (BMD) is decreased after daily treatment with teriparatide (13). In contrast, weekly treatment with teriparatide is unlikely to increase bone remodeling because neither an increase in bone resorption markers nor a decrease in cortical volumetric BMD is not found (14, 15).

Osteoporosis therapy: a novel insight from natural homeostatic system in the skeleton

The skeleton normally responds to mechanical environment to maintain the resulting elastic deformation (strain) of bone, while increased bone strength by an osteoporosis drug results in decreased bone strain. Thus, it can be hypothesized that the effect of osteoporosis therapy is limited by natural homeostatic system in the skeleton. This logic is consistent with the fact that there exists a powerful effect that returns bone mass to its pre-treatment level after the withdrawal of treatment with osteoporosis agents. The present hypothesis provides a new significant insight into the mechanisms by which osteoporosis drugs improve bone fragility. Here we briefly discuss the effects of teriparatide, romosozumab, and odanacatib on bones in animals and humans.

Calcium, proton pump inhibitors, and fracture risk

Dear Editor, The latest meta-analysis of observational studies regarding the association between proton pump inhibitors (PPIs) and fracture risk by Zhou and colleagues [1] showed that PPI therapy was linked to an increased incidence of hip fracture (15 studies; relative risk 1.26, 95% confidence interval 1.16 to 1.36), vertebral fracture (4 studies; 1.58, 1.38 to 1.82), and total fracture (10 studies; 1.33, 1.15 to 1.54). This is an important update because a PPI is one of the most frequently prescribed drugs in older people. Although the mechanisms by which use of PPIs increases fracture risk remain unclear, the authors did not support a long-standing explanation that the major cause would be the impairment of calcium absorption by PPIs [1]. On the basis of the latest research, we would like to discuss this topic further from a different point of view. There is no doubt that appropriate calcium as well as vitamin D is essential for bone health. In agreement with the earlier suggestion by Kanis and Passmore [2, 3], however, the latest systematic review and meta-analyses concluded that the effects of increasing calcium intake on areal bone mineral density (BMD) and fracture risk are limited [4–7]. Of note, this is compatible with accumulating data indicating no significant relation between PPI therapy and areal BMD [8] despite its possible inhibitory effect on intestinal calcium absorption. In contrast to PPIs, vitamin D is expected to increase calcium absorption in the gut. However, recent meta-analyses have consistently shown that its effects on areal BMD and fracture risk are also limited [9–13]. Furthermore, the latest randomized, double-blind, placebo-controlled clinical trial in postmenopausal women younger than 75 years with vitamin D insufficiency but not osteoporosis found that neither lowdose (800 IU daily) nor high-dose (50,000 IU twice monthly) vitamin D treatment for one year significantly changed areal BMD; the mean levels of serum 25-hydroxyvitamin D in the placebo, low-dose, and high-dose groups were 19, 28, and 56 ng/mL, respectively [14]. We have suggested that the effect of osteoporosis therapy is limited by skeletal adaptation to mechanical environment, because bone normally responds to mechanical loading to maintain resultant elastic deformation (strain) while an increase in bone strength by nutrients or drugs results in a decrease in bone strain from physical activity [15, 16]. This natural homeostatic system can explain that a small gain in areal BMD resulting from increasing calcium intake was observed during the first year but there was no further increase later [4] and is likely to work against “mild” mineral-related changes in bone material stiffness associated with PPIs as well as vitamin D [17–19]. In conclusion, we agree with the suggestion by the authors [1] that calcium malabsorption would not be a major cause of the association between PPI use and an increased risk of fractures. Potential mechanisms have been recently reviewed and there is evidence implying an increased risk of falling by PPIs [20]. Future research is required to clarify the mechanisms for the prevention of fractures in elderly patients with PPI therapy.

Warfarin use and fracture risk: an evidence-based mechanistic insight

Dear Editor, There is a long-standing debate on the association between use of warfarin, prescribed to millions of people to decrease their risk of clotting, and fracture risk [1]. In a large populationbased cohort in the UK, Misra and colleagues [2] found that warfarin use was not linked to an increase in fracture risk. Here, we would like to present an evidence-based, reasonable insight into the mechanisms by which this drug affects bone strength. Osteocalcin, the most abundant non-collagenous protein in bone, is incorporated into bone through vitamin K-dependent γ-carboxylation. Warfarin, a vitamin K antagonist, decreases osteocalcin content in bone and impairs bone material hardness in rats [3], which is consistent with data in mice that osteocalcin deficiency causes a decrease in bone tissue hardness [4]. Consistently, in older patients undergoing chronic therapy with oral vitamin K antagonists [5], undercarboxylated osteocalcin levels in blood were inversely related to cortical ultrasound velocity, an indicator of bone material quality, in agreement with a positive correlation between circulating levels of osteocalcin carboxylation and cortical ultrasound velocity in healthy children [6]. In contrast, however, skeletal strength depends on bone quality and quantity, and normally responds to mechanical environment to maintain the resulting elastic deformation of bone [7]; thus, higher bone mass but similar bone stiffness in osteocalcin-deficient mice indicates compensatory bone gain resulting from lower bone material hardness mentioned above [8]. Other examples of such a compensatory relation between bone quality and quantity include bigger skeleton in adult patients with hypophosphatemic osteomalacia characterized by hypomineralized bone [9], in accordance with children with hypophosphatemic rickets [10]. Notably, warfarininduced impairment of cortical bone material quality can be compensated by adaptation of cortical bone structure to mechanical loading in rats [3] and urinary γ-carboxyglutamate, a parameter of osteocalcin carboxylation, was inversely related to whole body bonemass change induced by jumping exercise in healthy premenopausal women [11]. A number of studies [12–20] have investigated the association between warfarin use and fracture risk in older patients, but their findings appear to be inconsistent. There is, however, one consistent result that warfarin use was essentially not linked to hip fracture risk. This fact can be reasonably explained by the compensation between bone quality and quantity because hip is a highly weight-bearing site compared to other sites such as the spine and rib [3]. To minimize potential methodological issues considered in earlier epidemiologic studies, the recent propensity score matched cohort [2] included more than 20,000 participants with new onset atrial fibrillation, by carefully selecting older men and women without prior warfarin use or prior fracture history and long-term use of warfarin, from The Health Improvement Network followed between 2000 and 2010; as a result, no significant association between warfarin use and hip, spine or wrist fracture was detected. Thus, on the basis of the present mechanistic insight relating to skeletal adaptation to mechanical loading, further investigation about the adverse effect of vitamin K antagonists on fracture risk could not be required in patients with normal physical activity, as suggested by the authors [2].

Romosozumab and blosozumab: alternative drugs of mechanical strain-related stimulus toward a cure for osteoporosis

In addition to other chronic diseases such as hypertension, hypercholesterolemia, and diabetes, a treat-to-target strategy was recently applied in rheumatoid arthritis and has now been discussed in osteoporosis. An important goal of osteoporosis therapy is normal risk of hip fracture associated with significant morbidity and mortality, but the anti-fracture efficacies of currently approved drugs are limited (1, 2). Although fundamental methods to effectively prevent osteoporotic fracture include pharmacological treatment of sarcopenia that results in improving bone fragility as well as reducing fall risk, the present article focuses on anti-sclerostin antibodies such as romosozumab and blosozumab, the investigational agents for osteoporosis, and provides new insights into their effects from natural homeostatic system in the skeleton.

Exercise for the skeleton in postmenopausal women: fundamental rules of mechanical strain-related stimulus

Dear Editor, The latest meta-analyses of the effects of exercise on areal bone mineral density (BMD) in postmenopausal women by Zhao and colleagues suggest that high-impact or weightbearing exercise is effective to increase areal BMD in the lumbar spine and hip [1] and that exercise and treatment with anti-resorptive osteoporosis drugs have an additive effect on areal BMD [2]. Here, we would like to confirm evidence to understand the optimum type of exercise for the improvement of skeletal fragility. As mentioned by the authors, the concept of skeletal adaptation to mechanical environment, known as Wolff’s law, was developed by Frost who proposed that the skeleton adapts to mechanical stimulation through control of bone strength by resultant elastic deformation (strain); this mechanical strainrelated feedback control is called the mechanostat [1]. Of note, accumulating experimental data in animals has shown at least eight fundamental rules of mechanical strain-related stimulus in the skeleton, engendered by habitual physical activity including exercise, as follows:

Skeletal Adaptation to Mechanical Strain: A Key Role in Osteoporosis

Wolff’s law indicates that mechanical loading plays a central role in controlling skeletal strength, as evidenced by marked bone gain in the dominant arms of professional tennis players or rapid bone loss in the weight-bearing sites of astronauts during space flight. Among various experimental methods of mechanical stimulation, the noninvasive axial loading model of the mouse tibia/fibula is useful to assess both cortical and trabecular compartments in vivo. The bone normally responds to local mechanical environment at each skeletal site to maintain resultant “elastic” deformation (strain), and this mechanical strain-related feedback control, known as the mechanostat, acts continuously throughout the physiologic range as recently shown in humans as well as animals. The response of the bone to mechanical loads would be impaired with aging but can be enhanced by intermittent treatment with parathyroid hormone. Increased bone strength by an osteoporosis drug results in decreased bone strain, suggesting that the effect of osteoporosis therapy is limited by skeletal adaptation to mechanical strain, which confirms the attractive efficacy of alternative drugs of mechanical strain-related stimulus such as anti-sclerostin antibodies. In contrast, although lower bone quality is linked to weaker bone strength, the mechanostat could compensate mineral-related, but not collagen-related, impairment of bone quality. Bone mechanobiology is important toward a cure for osteoporosis.