Remodeling Space Research Articles

Glucocorticoids disrupt longitudinal advance of cortical bone basic multicellular units in the rabbit distal tibia

Glucocorticoids (GCs) are the leading cause of secondary osteoporosis. The emerging perspective, derived primarily from 2D histological study of trabecular bone, is that GC-induced bone loss arises through the uncoupling of bone formation and resorption at the level of the basic multicellular unit (BMU), which carries out bone remodeling. Here we explore the impact of GCs on cortical bone remodeling in the rabbit model. Based upon the rapid reduction of bone formation and initial elevation of resorption caused by GCs, we hypothesized that the rate of advance (longitudinal erosion rate; LER) of cortical BMUs would be increased. To test this hypothesis we divided 20 female New Zealand White rabbits into four experimental groups: ovariohysterectomy (OVH), glucocorticoid (GC), OVH + GC and SHAM controls (n = 5 animals each). Ten weeks post-surgery (OVH or sham), and two weeks after the initiation of dosing (daily subcutaneous injections of 1.5 mg/kg of methylprednisolone sodium succinate in the GC-treated groups and 1 ml of saline for the others), the right tibiae were scanned in vivo using Synchrotron Radiation (SR) in-line phase contrast micro-CT at the Canadian Light Source. After an additional 2 weeks of dosing, the rabbits were euthanized and ex vivo images were collected using desktop micro-CT. The datasets were co-registered in 3D and LER was calculated as the distance traversed by BMU cutting-cones in the 14-day interval between scans. Counter to our hypothesis, LER was greatly reduced in GC-treated rabbits. Mean LER was lower in GC (4.27 μm/d; p < 0.001) and OVH + GC (4.19 μm/d; p < 0.001), while similar in OVH (40.13 μm/d; p = 0.990), compared to SHAM (40.44 μm/d). This approximately 90 % reduction in LER with GCs was also associated with an overall disruption of BMU progression, with radial expansion of the remodeling space occurring in all directions. This unexpected outcome suggests that GCs do not simply uncouple formation and resorption within cortical BMUs and highlights the value of the time-lapsed 4D approach employed.

Understanding basic multicellular unit activity in cortical bone through 3D morphological analysis: New methods to define zones of the remodeling space

The activity of basic multicellular units (BMU) in cortical bone is classically described as a sequential order of events— resorption, reversal and formation. This simplified portrayal of the remodeling process is pervasive despite the reported variability in remodeling space morphology. These variations may reflect meaningful nuances in BMU activity but methods to quantify 3D remodeling space morphology within the context of the cellular activity are currently lacking. This study developed new techniques to define zones of BMU activity based on the 3D morphology of remodeling spaces in rabbit cortical bone and integrated morphological data with the BMU longitudinal erosion rate (LER) to elucidate the spatial-temporal coordination of BMUs and estimate mineral apposition rate (MAR). The tibiae of New Zealand white rabbits (n = 5) were imaged in vivo using synchrotron radiation and two weeks later ex vivo with desktop microCT. The in vivo and ex vivo datasets were co-registered, and 27 remodeling spaces were identified at both timepoints. A radial profile representing the 3D morphology was the platform for partitioning the remodeling spaces into resorption, reversal and formation zones. Manual, automated and semi-automated partitioning approaches were compared, and the zone-segmentations were used to calculate the length, change in radius and slope of each zone. The manual approach most accurately defined the zones of idealized remodeling spaces with known dimensions (relative error = 0.9–9.2 %) while the semi-automated method reliably defined the zones in rabbit remodeling spaces (ICC = 0.85–1.00). Combining LER and the manually derived zone dimensions indicated that a BMU passes through a cross-section in approximately 18.8 days with resorption, reversal and formation taking 4.1, 2.2, and 12.5 days, respectively. MAR estimated by the 3D analysis was not significantly different than that determined with classic histomorphometry (p = 0.48). These techniques have the potential to assess dynamic parameters of bone resorption and formation, eliminate the need for fluorochrome labeling and provide a more comprehensive perspective of the remodeling process.

Endocortical Trabecularization in Acromegaly: The Cause for the Paradoxically Increased Vertebral Fracture Risk?

Growth hormone (GH) is nonphysiologically increased in acromegaly, stimulating target tissues directly and indirectly via insulin-like growth factor type 1 (IGF-1). Despite GH having anabolic effects on bone growth and renewal, the risk of vertebral fractures is paradoxically increased in acromegaly. We hypothesized that bone tissue compartments were differentially affected by hormonal alterations in active and controlled acromegaly. We aimed to study the effect of sex and gonadal status on long-term outcome of bone mass and structure to understand the biomechanical competence of bone. We followed 62 patients with newly diagnosed acromegaly longitudinally (median 4.8 years after pituitary surgery) to investigate changes assessed by dual X-ray absorptiometry (DXA), trabecular bone score (TBS), and hip structure analysis (HSA). At diagnosis, patients had increased bone mineral density (BMD) in most compartments compared with normative data (Z-scores). Conversely, TBS Z-score was decreased (Z = -0.64 (SD 1.73), p = 0.028). Following treatment of acromegaly, BMD increased further in compartments containing predominantly trabecular bone, such as the lumbar spine, in eugonadal and male subjects, while compartments with predominantly cortical bone, such as the hip and femoral neck, were unchanged. Total body measurements showed further increase in BMD independent of sex and gonadal status. TBS did not change. HSA revealed a significant decrease in cortical thickness in both sexes independent of gonadal status, whereas the overall size of bone (hip axis length and neck width) did not change over time. In conclusion, patients with acromegaly had increased bone mass and dimensions by DXA. Following normalization of disease activity, BMD increased mainly in compartments rich in trabecular bone, reflecting a closure of the remodeling space. However, HSA revealed a significant decrease in cortical thickness, implying endocortical trabecularization, potentially explaining the increased risk for incident vertebral fractures following treatment. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

RF06 | PSAT171 Impact of GH Administration on Skeletal Endpoints in Adults with Overweight/Obesity

Abstract Background Obesity is associated with relative growth hormone (GH) deficiency and increased fracture risk. We hypothesized that GH administration would improve bone endpoints in individuals with overweight/obesity. Methods 77 adults ages 18-65 years, BMI ≥25 kg/m2, and BMD T- or Z-score ≤ -1.0 were randomized in a double-blind protocol to daily subcutaneous GH or placebo for 18 months, targeting IGF-1 in the upper quartile of the age-appropriate normal range. There was a post-treatment observation period from 18-24 months. DXA and high-resolution peripheral quantitative CT were performed at baseline, 18 months and 24 months. Volumetric quantitative CT was performed at baseline and 18 months. Results are reported as mean ±SD or mean (95% confidence interval). Results There were no pretreatment differences between the GH (n=39) and placebo groups (n=38), including mean age (48±12y), BMI (33.1±5.7kg/m2) and BMD at any site. Forty-nine subjects (47% female) completed 18 months. P1NP, osteocalcin and CTX increased (p&amp;lt;0.005) and visceral adipose tissue decreased (p=0.04) at 18 months in the GH vs placebo group. Hip and radius aBMD, spine and tibial vBMD, tibial cortical thickness, and radial and tibial failure load decreased at 18 months in the GH vs placebo group (p&amp;lt;0.05). During the post-treatment observation period (18 to 24 months), total radius aBMD and tibia cortical thickness increased in the GH vs placebo group (p&amp;lt;0.05); there was also a trend toward an increase in total hip aBMD in the GH vs placebo group (p=0.06). At 24 months, none of the differences between the GH and placebo groups remained significant. There was a higher incidence of numbness and tingling (33% vs 8%, p=0.01) and joint pain or stiffness (33% vs 5%, p=0.003) in the GH vs placebo group. There were no other differences in adverse events between groups. Conclusions We demonstrated that GH administration for 18 months to individuals with overweight/obesity and low BMD decreased some measures of BMD, bone microarchitecture, and bone strength compared with placebo. None of these differences remained significant after 6 months off therapy. A longer duration of treatment, or a longer duration of observation post-treatment, may be necessary to see the expected biphasic decline and then increase in BMD reflecting an expanding remodeling space followed by mineralization that has previously been seen with GH administration in other populations, including individuals with and without GH deficiency. Although future investigation of the effects of GH on bone is required to assess the true long-term impact on skeletal integrity as well as fracture reduction, our study suggests that GH administration for 18 months to adults with overweight/obesity does not improve BMD, bone microarchitecture, or bone strength. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:12 p.m. - 1:17 p.m.

Impact of GH administration on skeletal endpoints in adults with overweight/obesity.

Overweight/obesity is associated with relative growth hormone (GH) deficiency and increased fracture risk. We hypothesized that GH administration would improve bone endpoints in individuals with overweight/obesity. An 18-month, randomized, double-blind, placebo-controlled study of GH, followed by 6-month observation. In this study, 77 adults (53% men), aged 18-65 years, BMI ≥ 25 kg/m2, and BMD T- or Z-score ≤ -1.0 were randomized to daily subcutaneous GH or placebo, targeting IGF1 in the upper quartile of the age-appropriate normal range. Forty-nine completed 18 months. DXA, volumetric quantitative CT, and high-resolution peripheral quantitative CT were performed. Pre-treatment mean age (48 ± 12 years), BMI (33.1 ± 5.7 kg/m2), and BMD were similar between groups. P1NP, osteocalcin, and CTX increased (P < 0.005) and visceral adipose tissue decreased (P = 0.04) at 18 months in the GH vs placebo group. Hip and radius aBMD, spine and tibial vBMD, tibial cortical thickness, and radial and tibial failure load decreased in the GH vs placebo group (P < 0.05). Between 18 and 24 months (post-treatment observation period), radius aBMD and tibia cortical thickness increased in the GH vs placebo group. At 24 months, there were no differences between the GH and placebo groups in bone density, structure, or strength compared to baseline. GH administration for 18 months increased bone turnover in adults with overweight/obesity. It also decreased some measures of BMD, bone microarchitecture, and bone strength, which all returned to pre-treatment levels 6 months post-therapy. Whether GH administration increases BMD with longer treatment duration, or after mineralization of an expanded remodeling space post-treatment, requires further investigation.

Kinetic reconstruction reveals time-dependent effects of romosozumab on bone formation and osteoblast function in vertebral cancellous and cortical bone in cynomolgus monkeys

Romosozumab, a humanized monoclonal sclerostin antibody under development for the treatment of osteoporosis, has a unique mechanism of action on bone—increasing bone formation and decreasing bone resorption. The effects on bone formation are transient, eliciting a rapid increase in bone formation that attenuates with continued treatment. Although bone formation attenuates, bone mineral density (BMD) continues to increase. To explore potential tissue-level mechanisms that could contribute to a progressive increase in spine BMD, we used kinetic reconstruction techniques to examine the effects of romosozumab on modeling and remodeling units in vertebral cancellous bone from adult cynomolgus monkeys administered romosozumab for 10 and 28weeks.The 10-week study duration captured a period of high modeling-based bone formation, and the 28-week study duration followed the self-regulation or attenuation of bone formation in cancellous bone that occurs with long-term treatment. Sequential fluorochrome labels applied for the kinetic reconstruction were also used to evaluate treatment effects on osteoblast function as early as 3weeks, and on bone formation and bone accrual in the vertebral cortex over 28weeks.Kinetic reconstruction of remodeling and modeling formation sites in vertebral cancellous bone revealed that romosozumab effected significant transient increases in mineral apposition rate in remodeling sites at week 3 that was not sustained with continued treatment. However, romosozumab treatment caused sustained improvement in fractional labeling of osteoid, an index of osteoblast efficiency, at remodeling formative sites at both weeks 10 and 28 that was the major contributor to significant increases in final wall thickness (W.Th) of remodeling packets. Remodeling W.Th matched the final W.Th of modeling packets at week 10. At both weeks 10 and 28, romosozumab significantly decreased eroded surface (ES/BS). At week 28, romosozumab also significantly reduced resorption period (Rs.P) and final resorption depth (Rs.De). The reduced final Rs.De combined with the increased W.Th resulted in a significant increase in bone balance (BB) at the level of the remodeling unit. Assessment of bone formation on the vertebral periosteal and endocortical surfaces following 28weeks of treatment revealed that romosozumab significantly increased bone formation on these surfaces, which had attenuated by week 28, resulting in significant increases in new periosteal and endocortical bone by week 28.These data suggest that multiple factors potentially contribute to the increase in spine BMD with romosozumab treatment. In the early period of treatment, increased modeling-based bone formation, increased W.Th at remodeling sites, a decrease in remodeling space secondary to decreased ES/BS in vertebral cancellous bone, and increased periosteal and endocortical bone formation in the vertebral cortex contribute to the early increase in spine BMD. Following the self-regulation of bone formation when modeling-based bone formation has attenuated, a decrease in remodeling space secondary to reduced ES/BS and a positive BB secondary to decreased final Rs.De and increased W.Th contribute to the progressive increase in spine BMD with long-term treatment.

Pitfalls in interpreting interventional studies for osteoporosis.

After adulthood, changes in the skeleton are slow and takes years for accruing or losing any appreciable amount of bone mass. Proper interpretation of studies that evaluate the effect of nutrients (like calcium, vitamin D) and anti-resorptive agents (like bisphosphonates) on bone mass is important so that the true effect of the agent is measured correctly. In this report, we are highlighting two issues of utmost importance for correctly interpreting interventional studies for osteoporosis. One issue is the bone remodelling transient (BRT). It refers to a transient change in bone mineral density (BMD) by any agent that reduces remodeling space temporarily. This change is, however, not sustained for a long period and can be misinterpreted as a true gain in bone mass. The second issue is difference between calcium balance and bone balance. Calcium balance is the difference between the amount of calcium ingested in a day and the amount of calcium lost in that day. Recommendations for dietary calcium intake are based on calcium balance studies that presume calcium balance as an equivalent for bone balance. However, these are two different entities and need to be distinguished. Dietary calcium requirements should be established by bone balance studies using bone densitometry, not by calcium balance studies.

대학교 실내 휴게 공간 계획 방향에 관한 연구 - K 대학교의 대학생 선호도 분석을 중심으로 -

University campus is confronted with a variety of educational circumstances. U-Campus and the changes in students' academic activities demand a remodeling of university campus. The purpose of this study is planning direction for a remodeling space in university. This study in particular focus on indoor student lounges for the students. A survey asked students about a preference of indoor student lounges. Four preferences; the physical characteristics, preference of furnitures and lighting, preference of behaviors and preference of space programs are classified through the analysis on advanced studies. The results show not only students' preference but also a preference of each four different departments students; Social science, Physical education, Natural sciences and Engineering. In conclusion, this study will suggest a concrete plan for the future direction of the indoor student lounges at this point increased the importance of the university indoor student lounges.

독거노인 공동생활시설의 리모델링에 관한 평가 연구 - 경기도 지역 사례를 중심으로 -

The purpose of this study was to analyze the remodeling of Carnation House, examine the current state of the spatial remodeling, and propose the future direction of the spatial remodeling of communal life facilities for the elderly living alone. To this end, experimental investigation, photograph shooting, and interviews with managers were performed, and a remodeling analysis was conducted by comparing the data before and after the remodeling. The study results can be summarized as below. First, as there is no standard for the remodeling of communal life facilities for the elderly living alone, related guidelines should be provided in the near future. Second, more fundamental approach to the remodeling should be made considering medical services for the elderly's safety, universal design plans, lifestyles of the elderly, and their use behaviors. Third, as communal life facilities for the elderly living alone normally have small spaces due to the remodeling by change of use, variable spatial planning should be performed for the elderly to utilize communal life facilities as multi-purpose and multi-functional spaces. Fourth, as the terrace space is an essential remodeling space needed for the elderly's rest, communication, and creation of profits, its remodeling should be realized in such a way that various programs can be utilized. Fifth, it turned out that the exterior remodeling could change the overall image of the facilities through new materials and colors.

Regional Acceleratory Phenomenon.

The regional acceleratory phenomenon (RAP) is a tissue reaction to a noxious stimulus that increases the healing capacities of the affected tissues. It is typical not only of hard tissues such as bone and cartilage, but also of soft tissues. The RAP is characterized by acceleration of the normal cellular activities, as an 'SOS' phenomenon of the body that has to respond to the new perturbation. In the alveolar bone, the RAP is characterized, at a cellular level, by increased activation of the basic multicellular units (BMUs), thereby increasing the remodeling space. At the tissue level, the RAP is characterized by the production of woven bone, with the typical unorganized pattern, that will be reorganized into lamellar bone at a later stage. In the alveolar bone, the RAP occurs typically in the healing process of the alveolar sockets after tooth extraction, in periodontal disease, after surgery and trauma and during orthodontic tooth movement. In relation to orthodontic tooth movement, the RAP can be seen as a tissue response to the mechanical cyclical perturbation that induces the formation of microdamage that has to be removed to avoid their accumulation and the following bone failure. The adaptation to the new orthodontically induced mechanical environment is ensured by an increased activation of the BMU that returns to normal levels after few months.

The effect of bovine parathyroid hormone withdrawal on MC3T3-E1 cell proliferation and phosphorus metabolism.

Hypocalcemia and hypophosphatemia are common complications after parathyroidectomy (PTX). Sudden removal of high circulating levels of parathyroid hormone (PTH) causes decreased osteoclastic resorption resulting in a decreased bone remodeling space. These phenomena are likely due to an increased influx of calcium and phosphorus into bone. However, there are currently no data to support this hypothesis. In this study, we found that PTX significantly reduced levels of PTH, calcium and phosphate. Compared with preoperative levels, after 1 year, postoperative PTH, calcium and phosphate levels were 295.6 ± 173.7 pg/mL (P < 0.05), 86.62 ± 15.98 mg/dL (P < 0.05) and 5.56 ± 2.03 mg/dL (P < 0.05), respectively. We investigated continuous bovine PTH administration as well as withdrawal of bovine PTH stimulation in the mouse osteoblast precursor cell line MC3T3-E1. MC3T3-E1 cells were cultured with continuous bovine PTH treatment for 20 days or with transient bovine PTH treatment for 10 days. High doses of continuous bovine PTH exposure strongly reduced cell proliferation, alkaline phosphatase activity and the number of mineralized calcium nodules. However, withdrawal of bovine PTH (100 ng/mL) significantly increased the number of mineralized calcium nodules and caused a rapid decline in calcium and phosphorus content of culture medium. In conclusion, continuous exposure to bovine PTH inhibited osteoblast differentiation and reduced the formation of mineralized nodules. However, this inhibition was removed and mineralized nodule formation resumed with withdrawal of bovine PTH. According to the results of our clinical examinations and in vitro experiments, we hypothesize that the sudden removal of high levels of PTH may cause an increased influx of calcium and phosphorus into bone after PTX.

Inhibition of sclerostin in the management of osteoporosis: results of a phase 2 clinical trial meet expectations.

Inhibition of sclerostin in the management of osteoporosis: results of a phase 2 clinical trial meet expectations.

Cortical porosity in children is determined by age-dependent osteonal morphology

IntroductionFracture rates in children are high. Cortical bone makes a major contribution to bone strength, determined by cortical geometry, mineralization and porosity. Of these, porosity remains least well explored. Since most cortical canals are part of an osteon, we examined osteons and their canals for age-related changes in numbers, size and shape in 87 iliac crest bone samples of subjects aged 0–25years, using histomorphometry. ResultsThree types of secondary osteons were identified: drifting, eccentric and concentric. 1. Drifting osteons predominated to the mid-teens, were large, asymmetrical, and had giant canals (remodeling space) with the resorption front drifting towards the marrow. The cause of drift remains unclear. Onset of formation appeared delayed, and commenced on the periosteum-facing surface. From the mid-teens numerical density of drifting osteons decreased, and so did porosity. 2. Eccentric osteons were smaller, more circular and had a small excentric canal; their numerical density gradually increased with age. 3. Concentric osteons (adult bone) were the smallest, most symmetrical osteons, had a small central canal, and markedly increased in numerical density from the mid-teens. Boys showed greater overall porosity and greater numerical density of drifting osteons, and later change to concentric osteons than girls. Whites had greater numerical density and greater areal density of resorption cavities than blacks. ConclusionsStructure of osteons and canals varied during growth. Large asymmetrical drifting osteons with giant active canals (remodeling space) predominated until the mid-teens and accounted for >70% of childhood cortical porosity. Thereafter smaller concentric (adult type) osteons increasingly predominated. Gender differences may relate to greater fracture rates in boys, and race differences to greater fracture rates in whites. The role of osteocyte-mediated mechanotransduction in osteonal structure and cortical porosity during growth warrants further exploration.

BMD improvements after operation for primary hyperparathyroidism

This study aims to quantify bone mineral density (BMD) changes following surgery in patients with primary hyperparathyroidism (PHPT) and to assess their relationship with clinical and biochemical variables. A historic cohort of 236 PHPT patients with DXA scans pre- and 1-year postoperatively, clinical data, and biochemical data was analyzed. The mean age was 60 years (range 19-86) and 81 % of the patients were women. A significant postoperative 2.6 % (95 % CI, 2.1; 3.1) increase in lumbar spine BMD was seen. The increase in BMD was positively associated with preoperative plasma PTH (p = 0.002), Ca(2+) (p < 0.001), and alkaline phosphatase (p = 0.014). Hip BMD increased 1.5 % (1.1; 1.9). The increase in BMD was positively associated with preoperative plasma PTH (p = 0.005) and Ca(2+) (p < 0.001) and inversely associated with plasma creatinine (p = 0.004) and age (p = 0.018). Total forearm BMD did not change significantly (-0.2 % (-0.5; 0.1)). An increase in forearm BMD was seen in 38 % of all patients, and the changes were positively associated with plasma PTH (p < 0.001) and Ca(2+) (p = 0.009). In all 91 patients with mild PHPT (plasma Ca(2+) < 1.45 mmol/l), there was a significant postoperative increase in spine BMD (1.9 % (1.2; 2.7)) and in hip BMD (1.0 % (0.4; 1.6)), but not in the forearm BMD (-0.3 % (-0.7; 0.2)). The postoperative BMD gain was higher in the hip and forearm in patients operated for adenomas compared with patients treated for hyperplasia. We found significant postoperative BMD improvements both at the hip and the spine. BMD improvements were also significant in mild cases. At all scan sites, there were positive associations between preoperative plasma PTH levels and postoperative BMD increases. The measured BMD changes may mainly be due to a decrease in PTH-induced bone turnover with refilling of the remodeling space.

Bone strength and surrogate markers: The first, second, and third fiddle

Bone strength and surrogate markers: The first, second, and third fiddle

Bone disease in primary hyperparathyrodism

Nowadays, primary hyperparathyroidism (PHPT) is mostly a mild disease. Overt skeletal manifestations are rare but decreased bone mineral density (BMD) can still be demonstrated. Even in mild cases, excess parathyroid hormone (PTH) increases bone turnover leading to bone loss particularly at cortical sites. Conversely, a relative preservation of cancellous bone has been shown by histomorphometric analyses and advanced imaging techniques. An increased fracture rate has been demonstrated in untreated patients with PHPT at peripheral sites and in the spine. Parathyroidectomy (PTx) is the definitive cure for PHPT. With the restoration of normal PTH, bone resorption is quickly tapered down, while bone formation proceeds at the level of bone multicellular units, which were activated prior to PTx. The rapid refilling of the enlarged remodeling space and the subsequent matrix mineralization will result in an increase in BMD at sites rich in trabecular bone, such as lumbar spine and hip, which mainly occurs during the first 6-12 months after PTx. Cortical bone is less responsive to PTX because of the low rate of bone turnover, but sensible increases in BMD at the distal third of the radius can be observed in the long term. PTx seems to decrease the risk of fractures but more data are needed before a definitive conclusion on this important matter can be reached. Treatment with bisphosphonates can be considered for patients with low BMD who do not undergo PTx. Two-year treatment with alendronate has been shown to decrease bone turnover markers and increase BMD at the lumbar spine and hip, but not at the distal radius. Cinacalcet stably decreased serum calcium levels across a broad range of PHPT severity, but no change in BMD occurred in patients treated for up to 5.5 years.

The Effect of Antiresorptives on Bone Quality

Currently, antiresorptive therapy in the treatment and prevention of osteoporosis includes bisphosphonates, estrogen replacement, selective estrogen receptor modulators (raloxifene), and denosumab (a human antibody that inactivates RANKL). The original paradigm driving the development of antiresorptive therapy was that inhibition of bone resorption would allow bone formation to continue and correct the defect. However, it is now clear increases in bone density account for little of the antifracture effect of these treatments. We examined the antifracture benefit of antiresorptives deriving from bone quality changes. We searched the archive of nearly 30,000 articles accumulated over more than 40years in our research center library using a software program (Refman™). Approximately 250 publications were identified in locating the 69 cited here. The findings document antiresorptive agents are not primarily anabolic. All cause a modest increase in bone density due to a reduction in the bone remodeling space; however, the majority of their efficacy is due to suppression of the primary cause of osteoporosis, ie, excessive bone remodeling not driven by mechanical need. All of them improve some element(s) of bone quality. Antiresorptive therapy reduces risk of fracture by improving bone quality through halting removal of bone tissue and the resultant destruction of microarchitecture of bone and, perhaps to some extent, by improving the intrinsic material properties of bone tissue. Information presented here may help clinicians to improve selection of patients for antiresorptive therapy by avoiding them in cases clearly not due to excessive bone remodeling.

Morphological analysis of bone dynamics and metabolic bone disease. Effects of parathyroid hormone on bone tissue

Parathyroid hormone (PTH) is a major hormonal regulator of calcium homeostasis. Continuous exposure of bone to PTH results in a net catabolic or resorptive response, whereas intermittent exposure to PTH leads to dramatic increases in bone formation and bone volume. Anabolic effects of PTH on bone have been demonstrated histologically in osteopenic animal models and in human osteoporosis. PTH increases the size of remodeling space and the number of basic multicellular units, resulting in a positive bone balance. PTH treatment also induces modeling bone formation at quiescent surfaces. PTH can increase and re-establish trabecular connectivity with a shift toward a more plate-like structure.

Are Osteoclasts Needed for the Bone Anabolic Response to Parathyroid Hormone?: A STUDY OF INTERMITTENT PARATHYROID HORMONE WITH DENOSUMAB OR ALENDRONATE IN KNOCK-IN MICE EXPRESSING HUMANIZED RANKL

PTH stimulates osteoblastic cells to form new bone and to produce osteoblast-osteoclast coupling factors such as RANKL. Whether osteoclasts or their activity are needed for PTH anabolism remains uncertain. We treated ovariectomized huRANKL knock-in mice with a human RANKL inhibitor denosumab (DMAb), alendronate (Aln), or vehicle for 4 weeks, followed by co-treatment with intermittent PTH for 4 weeks. Loss of bone mass and microarchitecture was prevented by Aln and further significantly improved by DMAb. PTH improved bone mass, microstructure, and strength, and was additive to Aln but not to DMAb. Aln inhibited biochemical and histomorphometrical indices of bone turnover,--i.e. osteocalcin and bone formation rate (BFR) on cancellous bone surfaces-, and Dmab inhibited them further. However Aln increased whereas Dmab suppressed osteoclast number and surfaces. PTH significantly increased osteocalcin and bone formation indices, in the absence or presence of either antiresorptive, although BFR remained lower in presence of Dmab. To further evaluate PTH effects in the complete absence of osteoclasts, high dose PTH was administered to RANK(-/-) mice. PTH increased osteocalcin similarly in RANK(-/-) and WT mice. It also increased BMD in RANK(-/-) mice, although less than in WT. These results further indicate that osteoclasts are not strictly required for PTH anabolism, which presumably still occurs via stimulation of modeling-based bone formation. However the magnitude of PTH anabolic effects on the skeleton, in particular its additive effects with antiresorptives, depends on the extent of the remodeling space, as determined by the number and activity of osteoclasts on bone surfaces.

Effects of combination treatment with alendronate and vitamin K2 on bone mineral density and strength in ovariectomized mice

Bisphosphonates increase bone mineral density (BMD) by suppressing remodeling space and elongating the duration of mineralization. Menatetrenone (vitamin K(2)) reduces the incidence of fractures by improving bone quality through enhanced gamma-carboxylation of bone glutamic acid residues of osteocalcin in osteoporotic patients. This study investigated the effects of combination treatment with alendronate (ALN) and vitamin K(2) on BMD and bone strength in ovariectomized (OVX) mice. Thirty-three female mice, 16 weeks of age, were assigned to four groups: (1) OVX-control group; (2) oral vitamin K(2) group; (3) subcutaneous ALN group; and (4) ALN + vitamin K(2) group. The treatment was started 4 weeks after OVX and continued for 4 weeks. BMD, geometric parameters measured by peripheral quantitative computed tomography, and mechanical strength at the femoral metaphysis and mid-diaphysis were evaluated after an 8-week treatment period. ALN alone significantly increased total BMD (20%, P < 0.05) and trabecular BMD (25%, P < 0.05), but not the mechanical parameters of the femur, compared with the OVX-control group. Combination treatment with ALN and vitamin K(2) increased not only total BMD (15%, P < 0.05) and trabecular BMD (32%, P < 0.05) but also maximum load (33%, P < 0.05) and breaking energy (25%, P < 0.05) of compression test at the distal metaphysis, and maximum load (20%, P < 0.05) and breaking force (33%, P < 0.05) of three-point bending test at the mid-diaphysis compared with the OVX-control group. These results suggest that ALN, alone or in combination with vitamin K(2), showed significant improvement in BMD, but that the combination treatment was more effective than ALN alone for improving bone strength in OVX mice.