Harmonization of Osteoporosis Guidelines: Paving the Way for Disrupting the Status Quo in Osteoporosis Management in the Asia Pacific

In the Asia Pacific (AP) region, osteoporosis and its consequence of fragility fractures are not widely recognized as a major public health problem. Several challenges including underdiagnosis and undertreatment exist. The Asia Pacific Consortium on Osteoporosis (APCO) is a nonpartisan and apolitical organization comprising musculoskeletal experts and stakeholders from both private and public sectors who have united to develop tangible solutions for these substantive challenges. APCO's vision is to reduce the burden of osteoporosis and fragility fractures in the AP region. Heterogeneity in both scope and recommendations among the available clinical practice guidelines (CPGs) contribute to the large osteoporosis treatment gap in the Asia Pacific. APCO has therefore developed a pan Asia-Oceania harmonized set of standards of care (The Framework), for the screening, diagnosis, and management of osteoporosis. First, a structured analysis of the 18 extant AP CPGs was completed. Subsequently, a prioritization of themes and agreement on fundamental principles in osteoporosis management were made through a Delphi process of consensus building. This approach, ensuring the opinions of all participating members were equally considered, was especially useful for a geographically diverse group such as APCO. It is hoped that the Framework will serve as a platform upon which new AP national CPGs can be developed and existing ones be revised. APCO is currently embarking on country-specific engagement plans to embed the Framework in clinical practice in the AP region. This is through partnering with regulatory bodies and national guidelines development authorities, through peer-to-peer health care professional education and by conducting path finder audits to benchmark current osteoporosis services against the Framework standards. The principles underpinning the harmonization of guidelines in the AP region can also be utilized in other parts of the world that have similar socioeconomic diversity and heterogeneity of healthcare resources. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Effects of Denosumab and Teriparatide Transitions on Bone Microarchitecture and Estimated Strength: the DATA‐Switch HR‐pQCT study

In postmenopausal osteoporosis, switching from teriparatide to denosumab results in continued bone mineral density (BMD) gains whereas switching from denosumab to teriparatide results in BMD loss. To assess the effects of these transitions on bone microarchitecture and strength, we performed high‐resolution peripheral QCT (HR‐pQCT) at the distal tibia and radius in postmenopausal osteoporotic women who received 24 months of teriparatide 20 μg daily followed by 24 months of denosumab 60 mg every 6 months, 24 months of denosumab followed by 24 months of teriparatide, or 24 months of both medications followed by 24 months of denosumab. The 77 women who completed at least one post‐switch visit are included in this analysis. Tibial cortical volumetric BMD (vBMD) increased between months 24 and 48 in the teriparatide‐to‐denosumab (net 48‐month change –0.8% ± 2.4%) and combination‐to‐denosumab groups (net 48‐month changes +2.4% ± 4.1%) but decreased in the denosumab‐to‐teriparatide group (net 48‐month change –3.4% ± 3.2%, p < 0.001 for all between‐group comparisons). Changes in total vBMD, cortical thickness, and estimated stiffness (by micro–finite element analysis [µFEA]) followed a similar pattern, as did changes at the radius. Conversely, tibial cortical porosity remained stable between months 24 and 48 in the teriparatide‐to‐denosumab and combination‐to‐denosumab groups (net 48‐month changes +7.2% ± 14.8% and –3.4% ± 12.1%, respectively) but increased in the denosumab‐to‐teriparatide group (net 48‐month change +16.2% ± 11.5%, p < 0.05 versus other groups). Trabecular vBMD changes did not differ among groups. Together, these findings demonstrate that in women treated with denosumab, switching to teriparatide is associated with a reduction in total and cortical vBMD, cortical thickness, and estimated strength, whereas switching to denosumab from teriparatide or combination therapy results in improvements in these parameters with the greatest improvements observed in women treated with combined therapy followed by denosumab. These findings strongly suggest that the use of teriparatide after denosumab should be avoided and that the use of combined teriparatide/denosumab followed by denosumab alone may be a useful treatment strategy in those with severe osteoporosis. © 2017 American Society for Bone and Mineral Research.     

Single‐ and Multiple‐Dose Randomized Studies of Blosozumab,a Monoclonal Antibody Against Sclerostin,in Healthy Postmenopausal Women

Two clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses (intravenous [iv] and subcutaneous [sc]) of blosozumab in postmenopausal women, including prior/current bisphosphonate (BP) users. In these phase 1, randomized, subject‐ and investigator‐blind, placebo‐controlled studies, subjects received escalating doses of blosozumab: single iv doses up to 750 mg, single sc doses of 150 mg, multiple iv doses up to 750 mg every 2 weeks (Q2W) for 8 weeks, multiple sc doses up to 270 mg Q2W for 8 weeks, or placebo. Six subjects were randomized to each dose in the single‐dose study (12 to placebo) and up to 12 subjects to each arm in the multiple‐dose study. Blosozumab was well tolerated with no safety concerns identified after single or multiple administrations up to 750 mg. Dose‐dependent responses were observed in sclerostin, N‐terminal propeptide of procollagen type 1, bone‐specific alkaline phosphatase, osteocalcin, C‐terminal fragment of type 1 collagen, and bone mineral density (BMD) after single and multiple (up to 5) administrations of blosozumab. There was up to a 3.41% (p = 0.002) and up to a 7.71% (p < 0.001) change from baseline in lumbar spine BMD at day 85 after single or multiple administrations of blosozumab, respectively. Prior BP use did not appear to have a clear impact on the effects of single doses of blosozumab when considering bone biomarker and BMD responses. Antibodies to blosozumab were detected by a screening assay, but no patterns with regard to dose or route of administration and no clear impact on blosozumab exposure or PD responses were identified. In summary, blosozumab was well tolerated and exhibited anabolic effects on bone. These findings support further investigation of blosozumab as a potential anabolic therapy for osteoporosis. © 2014 American Society for Bone and Mineral Research.     

Targeting the LRP5 Pathway Improves Bone Properties in a Mouse Model of Osteogenesis Imperfecta

The cell surface receptor low‐density lipoprotein receptor‐related protein 5 (LRP5) is a key regulator of bone mass and bone strength. Heterozygous missense mutations in LRP5 cause autosomal dominant high bone mass (HBM) in humans by reducing binding to LRP5 by endogenous inhibitors, such as sclerostin (SOST). Mice heterozygous for a knockin allele (Lrp5^p.A214V) that is orthologous to a human HBM‐causing mutation have increased bone mass and strength. Osteogenesis imperfecta (OI) is a skeletal fragility disorder predominantly caused by mutations that affect type I collagen. We tested whether the LRP5 pathway can be used to improve bone properties in animal models of OI. First, we mated Lrp5^+/p.A214V mice to Col1a2^+/p.G610C mice, which model human type IV OI. We found that Col1a2^+/p.G610C;Lrp5^+/p.A214V offspring had significantly increased bone mass and strength compared to Col1a2^+/p.G610C;Lrp5^+/+ littermates. The improved bone properties were not a result of altered mRNA expression of type I collagen or its chaperones, nor were they due to changes in mutant type I collagen secretion. Second, we treated Col1a2^+/p.G610C mice with a monoclonal antibody that inhibits sclerostin activity (Scl‐Ab). We found that antibody‐treated mice had significantly increased bone mass and strength compared to vehicle‐treated littermates. These findings indicate increasing bone formation, even without altering bone collagen composition, may benefit patients with OI. © 2014 American Society for Bone and Mineral Research.     

Diabetes and Deficits in Cortical Bone Density,Microarchitecture, and Bone Size: Framingham HR‐pQCT Study

Older adults with type 2 diabetes (T2D) tend to have normal or greater areal bone mineral density (aBMD), as measured by DXA, than those who do not have diabetes (non‐T2D). Yet risk of fracture is higher in T2D, including 40% to 50% increased hip fracture risk. We used HR‐pQCT to investigate structural mechanisms underlying skeletal fragility in T2D. We compared cortical and trabecular bone microarchitecture, density, bone area, and strength in T2D and non‐T2D. In secondary analyses we evaluated whether associations between T2D and bone measures differed according to prior fracture, sex, and obesity. Participants included 1069 members of the Framingham Study, who attended examinations in 2005 to 2008 and underwent HR‐pQCT scanning in 2012 to 2015. Mean age was 64 ± 8 years (range, 40 to 87 years), and 12% (n = 129) had T2D. After adjustment for age, sex, weight, and height, T2D had lower cortical volumetric BMD (vBMD) (p < 0.01), higher cortical porosity (p = 0.02), and smaller cross‐sectional area (p = 0.04) at the tibia, but not radius. Trabecular indices were similar or more favorable in T2D than non‐T2D. Associations between T2D and bone measures did not differ according to sex or obesity status (all interaction p > 0.05); however, associations did differ in those with a prior fracture and those with no history of fracture. Specifically, cortical vBMD at the tibia and cortical thickness at the radius were lower in T2D than non‐T2D, but only among those individuals with a prior fracture. Cortical porosity at the radius was higher in T2D than non‐T2D, but only among those who did not have a prior fracture. Findings from this large, community‐based study of older adults suggest that modest deterioration in cortical bone and reductions in bone area may characterize diabetic bone disease in older adults. Evaluation of these deficits as predictors of fracture in T2D is needed to develop prevention strategies in this rapidly increasing population of older adults. © 2017 American Society for Bone and Mineral Research.     

SIRT1/HERC4 Locus Associated With Bisphosphonate‐Induced Osteonecrosis of the Jaw: An Exome‐Wide Association Analysis

Osteonecrosis of the jaw (ONJ) is a rare, but serious drug side effect, mainly associated with the use of intravenous (iv) bisphosphonates (BPs). The purpose of this study was to identify genetic variants associated with ONJ in patients of European ancestry treated with iv BPs using whole‐exome sequencing (WES). The WES phase 1 included 44 multiple myeloma patients (22 ONJ cases and 22 controls) and WES phase 2 included 17 ONJ patients with solid tumors. Multivariable logistic regression analysis was performed to estimate the odds ratios (ORs) and 95% confidence intervals (CI), adjusting for age, sex, and principal components for ancestry. Meta‐analysis of WES phase 1 and 2 was performed to estimate the combined ORs. In silico analyses were then performed to identify expression quantitative loci (eQTL) single‐nucleotide polymorphisms (SNPs) that are in high linkage disequilibrium (LD) with the top SNPs. The associations of the potentially functional SNPs were replicated and validated in an independent case‐control study of 48 patients of European ancestry treated with iv BPs (19 ONJ cases and 29 controls). The top SNPs in the exome‐wide association meta‐analysis were two SNPs on chromosome 10: SIRT1 SNP rs7896005 and HERC4 SNP rs3758392 with identical OR of 0.07 (0.01–0.46; p = 3.83 × 10^?5). In the in silico functional analyses, two promoter region SNPs (rs7894483 and rs3758391) were identified to be in high LD with the index SNPs and are eQTLs for SIRT1 gene in whole blood in the GTEx database. The ORs were 0.30 (0.10–0.88), 0.26 (0.12–0.55), and 0.26 (0.12–0.55) for the WES top SNP rs7896005 and two promoter SNPs rs7894483 and rs3758391, respectively, in the replication sample. In summary, we identified the SIRT1/HERC4 locus on chromosome 10 to be associated with iv BP‐induced ONJ and two promoter SNPs that might be the potential genetic markers for this association. © 2017 The Authors.Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

Intestinal Calcium Absorption Decreases Dramatically After Gastric Bypass Surgery Despite Optimization of Vitamin D Status

Roux‐en‐Y gastric bypass (RYGB) surgery has negative effects on bone, mediated in part by effects on nutrient absorption. Not only can RYGB result in vitamin D malabsorption, but the bypassed duodenum and proximal jejunum are also the predominant sites of active, transcellular, 1,25(OH)₂D‐mediated calcium (Ca) uptake. However, Ca absorption occurs throughout the intestine, and those who undergo RYGB might maintain sufficient Ca absorption, particularly if vitamin D status and Ca intake are robust. We determined the effects of RYGB on intestinal fractional Ca absorption (FCA) while maintaining ample 25OHD levels (goal ≥30 ng/mL) and Ca intake (1200 mg daily) in a prospective cohort of 33 obese adults (BMI 44.7 ± 7.4 kg/m²). FCA was measured preoperatively and 6 months postoperatively with a dual stable isotope method. Other measures included calciotropic hormones, bone turnover markers, and BMD by DXA and QCT. Mean 6‐month weight loss was 32.5 ± 8.4 kg (25.8% ± 5.2% of preoperative weight). FCA decreased from 32.7% ± 14.0% preoperatively to 6.9% ± 3.8% postoperatively (p < 0.0001), despite median (interquartile range) 25OHD levels of 41.0 (33.1 to 48.5) and 36.5 (28.8 to 40.4) ng/mL, respectively. Consistent with the FCA decline, 24‐hour urinary Ca decreased, PTH increased, and 1,25(OH)₂D increased (p ≤ 0.02). Bone turnover markers increased markedly, areal BMD decreased at the proximal femur, and volumetric BMD decreased at the spine (p < 0.001). Those with lower postoperative FCA had greater increases in serum CTx (ρ = ?0.43, p = 0.01). Declines in FCA and BMD were not correlated over the 6 months. In conclusion, FCA decreased dramatically after RYGB, even with most 25OHD levels ≥30 ng/mL and with recommended Ca intake. RYGB patients may need high Ca intake to prevent perturbations in Ca homeostasis, although the approach to Ca supplementation needs further study. Decline in FCA could contribute to the decline in BMD after RYGB, and strategies to avoid long‐term skeletal consequences should be investigated. © 2015 American Society for Bone and Mineral Research.     

Nocturnal hyperactivity, increased social novelty preference and delayed extinction of fear responses in post-weaning socially isolated mice

When rodents are reared in isolation from young age onwards, they manifest a number of behavioural alterations in adulthood. Since some of these alterations resemble symptoms of psychiatric disorders, the post-weaning social isolation (ISO) manipulation is often applied to create rodent models of these disorders. In rats, ISO effects have been thoroughly characterised, but in mice they are less well documented. Therefore, we further evaluated behaviour of adult ISO mice with a test battery that focussed on abnormalities relevant to schizophrenia. We found that ISO mice were hyperactive during the dark phase. Also, ISO mice showed alterations in magnitude, habituation and prepulse-inhibition of the acoustic startle reflex, increased anxiety, increased social preference and changes in extinction of fear responses. We did not observe increased sensitivity to locomotor-activating effects of amphetamine. It is concluded that ISO of mice might serve as a useful model to test further hypotheses regarding pathogenesis occurring at specific developmental timeframes.     

The effects of preweaning manganese exposure on spatial learning ability and p-CaMKIIα level in the hippocampus

BackgroundThe effects and mechanisms of preweaning Manganese (Mn) exposure on cognitive dysfunction remain unclear.ObjectiveThis study evaluated the effects of preweaning Mn exposure on spatial learning and memory as well as the protein expression of CaMKIIα and p-CaMKIIα.MethodsWe treated neonate rats with Mn²⁺ doses of 0 (control group), 10, 20 and 30 mg of Mn²⁺ per kg body weight (Mn-exposed groups) over postnatal day (PND) 1–21 by intraperitoneal injection. The ability of spatial learning and memory was tested on PND 22 using the Morris water maze (MWM), while the protein expressions of CaMKIIα and p-CaMKIIα in the hippocampus were evaluated by Western blotting. The levels of Mn in the blood and hippocampus were measured by inductively coupled plasma-mass spectrometry (ICP-MS).ResultsThe rats in Mn-exposed groups showed a significant delay in spatial learning ability on the third day of the MWM without dose-dependent differences, but there was no effect on the spatial memory ability. p-CaMKIIα, but not CaMKIIα protein expression significantly reduced in the Mn-exposed group.ConclusionThese findings suggested that the inhibition of p-CaMKIIα could be one of the mechanisms involved in the occurrence of Mn-induced cognitive impairments.