Patient-reported experience with Fabry disease and its management in the real-world setting: results from a double-blind, cross-sectional survey of 280 respondents.

BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disorder with a heterogeneous clinical presentation. Patients with FD may exhibit early signs/symptoms including neuropathic pain, gastrointestinal complaints, and dermatologic manifestations. FD may ultimately progress to renal, neurologic, and cardiac dysfunction. Current treatments for FD have significantly improved the management and outcomes for patients with FD, but important clinical and convenience limitations still exist. METHODS: To illuminate the impact of FD on daily life from the patient's perspective, we asked adult patients (≥ 18 years old) with FD in the United States and Canada to complete a 33-question online survey to assess patient-reported disease severity, management, and treatment outcomes. RESULTS: A total of 280 respondents with FD completed the survey; they had a mean age of 47 years, and 68% (191/280) were women. Most were currently receiving FD treatment (84%, 234/280) with enzyme replacement therapy (ERT) (89%, 208/234) or chaperone therapy (11%, 26/234). Common symptoms included low energy/fatigue (72%, 201/280), tingling (62%, 174/280) or pain in the hands/feet (60%, 168/280), ringing in ears/hearing loss (54%, 151/280), general body pains/pain crises (51%, 143/280), and abdominal/stomach pain (50%, 140/280). More than half (51%, 144/280) of respondents reported their symptoms as bothersome (38%, 106/280) or difficult to control (14%, 38/280). Temporary symptom worsening between infusions was reported by about half of respondents: 51% (108/211) currently receiving ERT and 48% (14/29) previously receiving ERT. Only 48% (59/122) of respondents reported their symptom worsening to their physician. Of those who reported it, 41% (24/59) said that their physician prescribed medication to manage their symptoms or changed their treatment regimen. CONCLUSIONS: Our analysis highlights the gap between current standard-of-care in disease monitoring and patient perception of disease progression among patients with FD. This information may be helpful for healthcare providers and drug developers seeking to improve the care of patients with FD by addressing unmet needs of high relevance.

Navigating the Complexity of Chronic Graft-vs-Host Disease: Canadian Insights into Real-World Treatment Sequencing.

BACKGROUND: Graft-vs-Host Disease (GVHD) is a donor immune-mediated syndrome occurring in patients who undergo an allogeneic hematopoietic cell transplant (HCT). Chronic GVHD (cGVHD) presents with complications of variable severity. Corticosteroids are standard first-line (1L) treatment, but the sequence after 1L is unclear with the availability of new treatments. This research aimed to understand real-world treatment sequencing for cGVHD. METHODS: This retrospective study investigated adult patients across 7 treatment sites in Canada who had received an allogeneic HCT >18 months prior to the study, experienced cGVHD, and received systemic treatment, including extracorporeal photopheresis (ECP). RESULTS: A total of 77 cases were reviewed retrospectively (median age = 51 (IQR 41-62), 51% female). 59 patients remained on active systemic treatment, and among this group, the most common treatments in use were corticosteroids (47%) and ruxolitinib (47%). One patient died, and 17 patients were on non-systemic treatment after complications resolved. The median lines of treatment (LOT) received was 2 (IQR 1-3), with 39% of patients having received >2 LOT. Among patients with lung complications (n = 24), 41% had received 3 or more LOT. Among patients with scleroderma (n = 22), 77% had received 3 or more LOT, 23% of which had received 6 or more unique treatments. CONCLUSIONS: The first treatment given to cGVHD patients was corticosteroids. Ruxolitinib was the most used second-line treatment. About 40% of cGVHD patients received >2 treatments, and scleroderma was associated with more LOT. There is a need for more effective cGVHD treatment options when early treatments fail to resolve complications.

The Impact of Suboxone's Market Exclusivity on Cost of Opioid Use Disorder Treatment.

BACKGROUND: Buprenorphine-naloxone is an essential part of the response to opioid poisoning rates in North America. Manipulating market exclusivity is a strategy manufacturers use to increase profitability, as evidenced by Suboxone in the USA. OBJECTIVE: To investigate excess costs of buprenorphine-naloxone due to unmerited market exclusivity (no legal patent or data protection) in Canada. METHODS: Using controlled interrupted time-series, this study examined changes in the cost of buprenorphine-naloxone before and after the first generics were listed on public formularies. Methadone cost was the control. Public data from the Canadian Institute of Health Information in British Columbia, Manitoba, and Saskatchewan were used. All buprenorphine-naloxone and methadone claims (2010-2019) accepted for payment by the provincial drug plan/programme were collected. Primary outcome was mean cost per mg of buprenorphine-naloxone after the first listing of generics. RESULTS: Mean cost per mg of buprenorphine-naloxone before the first listing of generics was $1.21 CAD in British Columbia, $1.27 CAD in Manitoba, and $0.85 CAD in Saskatchewan. Following the introduction of generics, the cost per mg decreased by $0.22 CAD (95% CI - 0.33 to - 0.10; p = 0.0014) in British Columbia, $0.36 CAD (95% CI - 0.58 to - 0.13; p = 0.004) in Manitoba, and $0.27 CAD (95% CI - 0.50 to - 0.05; p = 0.03) in Saskatchewan. Mean cost per mg decreased by $0.26 CAD (95% CI - 0.38 to - 0.13; p = 0.0004) after a third generic was introduced in British Columbia. Excess costs to public formularies during the 4- to 5-year period prior to the listing of generics were $1,992,558 CAD in British Columbia, $80,876 CAD in Manitoba, and $4130 CAD in Saskatchewan. If buprenorphine-naloxone cost $0.61 CAD (mean cost after the third generic entered) instead of $1.21 CAD per mg during the pre-generics period, public payers in British Columbia could have saved $5,016,220 CAD between 2011 and 2015. CONCLUSIONS: Unmerited 6 years of market exclusivity for brand-name buprenorphine-naloxone in Canada resulted in substantial excess costs. There is an urgent need to implement policies that can help reduce costs for high-priority drugs in Canada.

Intake of mother's milk by very-low-birth-weight infants and variation in DNA methylation of genes involved in neurodevelopment at 5.5 years of age.

BACKGROUND: Mechanisms responsible for associations between intake of mother's milk in very-low-birth-weight (VLBW, <1500 g) infants and later neurodevelopment are poorly understood. It is proposed that early nutrition may affect neurodevelopmental pathways by altering gene expression through epigenetic modification. Variation in DNA methylation (DNAm) at cytosine-guanine dinucleotides (CpGs) is a commonly studied epigenetic modification. OBJECTIVES: We aimed to assess whether early mother's milk intake by VLBW infants is associated with variations in DNAm at 5.5 y, and whether these variations correlate with neurodevelopmental phenotypes. METHODS: This cohort study was a 5.5-y follow-up (2016-2018) of VLBW infants born in Ontario, Canada who participated in the Donor Milk for Improved Neurodevelopmental Outcomes trial. We performed an epigenome-wide association study (EWAS) to test whether percentage mother's milk (not including supplemental donor milk) during hospitalization was associated with DNAm in buccal cells during early childhood (n = 143; mean ± SD age: 5.7 ± 0.2 y; birth weight: 1008 ± 517 g). DNAm was assessed with the Illumina Infinium MethylationEPIC array at 814,583 CpGs. In secondary analyses, we tested associations between top-ranked CpGs and measures of early childhood neurodevelopment, e.g., total surface area of the cerebral cortex (n = 41, MRI) and Full-Scale IQ (n = 133, Wechsler Preschool and Primary Scale of Intelligence-IV). RESULTS: EWAS analysis demonstrated percentage mother's milk intake by VLBW infants during hospitalization was associated with DNAm at 2 CpGs, cg03744440 [myosin XVB (MYO15B)] and cg00851389 [metallothionein 1A (MT1A)], at 5.5 y (P < 9E-08). Gene set enrichment analysis indicated that top-ranked CpGs (P < 0.001) were annotated to genes enriched in neurodevelopmental biological processes. Corroborating these findings, DNAm at several top identified CpGs from the EWAS was associated with cortical surface area and IQ at 5.5 y (P < 0.05). CONCLUSIONS: In-hospital percentage mother's milk intake by VLBW infants was associated with variations in DNAm of neurodevelopmental genes at 5.5 y; some of these DNAm variations are associated with brain structure and IQ.This trial was registered at isrctn.com as ISRCTN35317141 and at clinicaltrials.gov as NCT02759809.

Diet Quality and Cognitive Performance in Children Born Very Low Birth Weight.

Children born very low birth weight (VLBW, <1,500 g) are at high risk for cognitive and academic difficulties later in life. Although early nutrition (e.g., breastfeeding) is positively correlated with IQ in children born VLBW, the association between dietary intake in childhood and cognitive performance is unknown. Thus, our study is the first to investigate the relationship between diet quality, as measured by the Healthy Eating Index-2010 (HEI-2010) and cognitive performance in a Canadian cohort of 5-year-old children born VLBW (n = 158; 47% female). Diet quality was measured using two 24-h diet recalls obtained from parents and cognitive performance was assessed using the Wechsler Preschool and Primary Scale of Intelligence-IV (WPPSI-IV). To account for additional sociodemographic factors that could influence neurodevelopment, linear regression analyses were adjusted for sex, household income above/below the poverty line, maternal education, birth weight and breastfeeding duration. Mean ± SD HEI-2010 score was 58.2 ± 12.4, with most children (67%) having diets in "need of improvement" (scores 51-80). HEI-2010 scores were not significantly associated with IQ or any other WPPSI-IV composite score. Significant predictors of IQ in our model were birth weight, sex, and maternal education. Our findings emphasize the important role of maternal education and other sociodemographic factors on neurodevelopment in children born VLBW. Further, despite not finding any significant association between HEI-2010 scores and IQ, our results highlight the need to improve diet quality in young children born VLBW. Further research is needed to confirm the impact of diet quality on cognitive performance in this vulnerable population.

Permissive regulation: A critical review of the regulatory history of buprenorphine formulations in Canada.

Suboxone (buprenorphine-naloxone) is an opioid product approved in the US and Canada for the treatment of opioid use disorder. The drug is considered an important response to the opioid overdose epidemic with consistent calls for wider prescribing and deregulation. The history of Suboxone regulation in Canada has not been critically examined. Part of the rationale for doing so stems from the US regulatory experience, with documented irregularities, or what some have called abuses, that support profit-making by Suboxone's manufacturers. This regulatory analysis allows us to determine how opportunities to address health crises through drug innovation are managed at a federal level. We used public drug and patent registries to critically examine Suboxone's Canadian history. First, we investigated Suboxone's entry into the Canadian market to understand how it achieved market exclusivity. Second, we examined Health Canada's risk mitigation process to address extramedical use and diversion to understand the intersection of regulation and brand promotion. Insights from these two analyses were then extended to the recent approval of two related buprenorphine-containing products and their specific pathways to Canadian market exclusivity. We identified inconsistencies in Suboxone's regulatory history that suggest Health Canada's functions of health protection and promotion were compromised in favour of an "innovations" agenda that supports profit-making. Despite six years of market exclusivity in Canada, there was no evidence suggesting Suboxone achieved formal exclusivity (i.e., through patent or data protection). Health Canada's process to address safety concerns of Suboxone were compromised by reliance on the manufacturer to carry out post-market education, allowing the manufacturer to create and market a branded "education" program for its product. Similar inconsistencies have afforded market exclusivity for two related products despite marginal innovation. These analyses reveal a case of permissive regulation, where principles of health protection are compromised by economic imperatives. Such a regulatory approach has the potential to adversely impact public health due to unnecessarily high costs for medicines deemed essential to stem a major health crisis. Alternative pharmaceutical policies are urgently needed to safely and efficiently expand treatment access for opioid use disorder.

Social-emotional functioning and dietary intake among children born with a very low birth weight.

Very low birth weight (VLBW, <1500 g)  infants are at an elevated risk of neurodevelopmental disorders, later obesity and cardiometabolic disease; if and how neurodevelopmental disorders impact chronic disease risk is poorly understood. The most common neurodevelopmental disorders experienced by VLBW children are those of social-emotional functioning. We compared dietary patterns and body composition between VLBW children with poor vs. typical social-emotional functioning using linear mixed models adjusted for sex, gestational age, cognitive impairment, parental education, and body mass index (BMI). VLBW children (n=158) attending the Donor Milk for Improved Neurodevelopmental Outcomes trial with 5.5-year follow-up participated. Poor social-emotional functioning was based on standardized parent-rated questionnaires and/or parent-reported physician diagnosis of autism spectrum or attention-deficit/hyperactivity disorders. Most children had diets categorized as "needs improvement" (67%) or "poor" (27%) and 29% of children exhibited poor social-emotional functioning. Poor social-emotional functioning was positively associated with 100% fruit juice (ß=0.3 cup equivalents/day; 95% CI 0.1, 0.5) and energy intake (ß=118.1 kcal/day; 95% CI 0.9, 235.2). Children with poor social-emotional functioning were more likely to have a limited food repertoire (p=0.02), but less likely to exceed dietary fat recommendations (p=0.04). No differences in overall diet quality or body composition were observed. Diet counselling and research are essential to improving the nutrition of VLBW children to mitigate chronic disease risk. Trial registration - Optimizing Mothers' Milk for Preterm Infants Program of Research: Study 1 - Impact of Donor Milk at Kindergarten, NCT02759809, https://clinicaltrials.gov/ct2/show/NCT02759809. Novelty: Overall diet quality and body composition did not differ between VLBW children with poor vs. typical social-emotional functioning. Most had diets "needing improvement" or "poor" according to the Healthy Eating Index-2010. Diet counselling may help mitigate chronic disease risk in this vulnerable population.

Associations between Diet Quality and Body Composition in Young Children Born with Very Low Body Weight.

BACKGROUND: Very low birth weight (VLBW; <1500 g) infants have increased adiposity and metabolic disease risk in adulthood. Limited evidence suggests low-quality childhood diets are a predisposing risk factor. Despite this, to our knowledge no study has yet examined associations between diet quality and body composition in VLBW individuals. OBJECTIVE: The objective of this study was to determine associations between Healthy Eating Index-2010 (HEI-2010) scores and consumption of fruits/vegetables, added sugars, and macronutrients with body composition in 5.5-y-old children born VLBW. We hypothesized HEI-2010 scores were inversely associated with adiposity. METHODS: This cohort study leveraged the 5.5-y follow-up to the Donor Milk for Improved Neurodevelopmental Outcomes randomized controlled trial. From June 2016 to July 2018, participants attended a follow-up visit at The Hospital for Sick Children, Canada, or were visited in their home. All 316 surviving infants from the trial were eligible, and the caregivers of 158 children (50%; 53% male) consented to follow-up. Diet quality (HEI-2010) and usual intake of fruits/vegetables, added sugars, and macronutrients were determined from two 24-h dietary recalls (ASA24). Linear regressions evaluated associations of diet with BMI (kg/m2) and waist circumference z-scores, total fat, fat-free mass (air displacement plethysmography), and skinfolds. RESULTS: Mean ± SD age at follow-up was 5.7 ± 0.2 y, birth weight was 1013 ± 264 g, and gestational age was 27.9 ± 2.5 wk. Dietary data and BMI z-scores were available for all children; 123 completed air displacement plethysmography. HEI-2010 score was 58.2 ± 12.4 out of 100, and 27% of children had poor quality diets (scores ≤50). HEI-2010 scores were inversely associated with BMI z-score, but only in children with obese mothers. A 10-point increase in HEI-2010 score was associated with reduced BMI (ß: -0.5 SD; 95% CI: -0.7, -0.2) and subscapular (-0.3 SD; 95% CI: -0.6, -0.06) z-scores. CONCLUSIONS: Improving diet quality in children born VLBW with obese mothers may be an important strategy to prevent excess adiposity. This trial was registered at clinicaltrials.gov as Optimizing Mothers' Milk for Preterm Infants (OptiMoM) Program of Research: Study 1-Impact of Donor Milk at Kindergarten, NCT02759809.

Lean mass accretion in children born very low birth weight is significantly associated with estimated changes from sedentary time to light physical activity.

BACKGROUND: Few studies have investigated how lifestyle is associated with body composition in children born very low birth weight (VLBW, <1500 g), a population at increased risk of obesity and metabolic syndrome in later life. OBJECTIVES: Determine how time spent in physical activity, sedentary time, and sleep are associated with body composition in children born VLBW. METHODS: In this prospective cohort study of 5.5-year-old children born VLBW, height, weight, body composition (skinfolds, air displacement plethysmography), and 7 days of movement data (logbooks and accelerometers) were collected. RESULTS: Of 158 participants, 53% were male, and mean (SD) birth weight was 1013 (264) g. Only 52% achieved 60 minutes/day of moderate-to-vigorous physical activity, but 96% achieved sleep recommendations. Reallocating 30 minutes of sedentary time to light physical activity (LPA) was associated with 0.20 kg/m2 (95% CI, 0.02 to 0.37) greater fat-free mass index. An equivalent inverse association was found when reallocating LPA to sedentary time. No associations were found for other movement behaviours. CONCLUSIONS: Promoting LPA and reducing sedentary time may be an important strategy in reducing the elevated risk of obesity and metabolic syndrome amongst those born VLBW by supporting lean mass accretion. Funded by CIHR (FHG 129919) and SickKids Restracomp.

Vitamin D: Insufficiency, Uncertainty and Achievability.

Vitamin D is a prohormone that is essential to good health. As very few foods (fish, egg yolks, milk) are rich in vitamin D, the main source of the vitamin is synthesized in the skin in the presence of ultraviolet B rays from sunlight. However, due to Canada's northern latitude, sufficient amounts of vitamin D cannot be synthesized using sunlight during the fall and winter months and, consequently, there is a concern that many Canadians are not achieving adequate levels of vitamin D. A wide array of inconsistent evidence derived from serum and dietary assessments has been published and the results are inconclusive. This paper serves to outline the issues and challenges regarding nationwide intervention strategies such as fortification to increase vitamin D intake in the Canadian population. Given the potential for excessive intakes and the lack of informed Canadian data, implementing an intervention to increase vitamin D intake in the entire population may be irresponsible; however, further investigation of vitamin D intakes in certain subgroups of the Canadian population is warranted.

Adiposity and Fat-Free Mass of Children Born with Very Low Birth Weight Do Not Differ in Children Fed Supplemental Donor Milk Compared with Those Fed Preterm Formula.

BACKGROUND: Many mothers of very-low-birth-weight (VLBW) infants (<1500 g) are unable to provide sufficient breast milk, and supplemental pasteurized donor human milk (donor milk) or preterm formula is required. The composition of donor milk differs from that of mother's milk and infants fed with donor milk often exhibit slower growth during hospitalization. The long-term impact of nutrient-enriched donor milk on growth, body composition, or blood pressure is unknown. OBJECTIVE: We aimed to determine the effects of nutrient-enriched donor milk compared with preterm formula on growth, body composition, and blood pressure of children born preterm and with VLBW. Associations with in-hospital mother's milk intake were explored. METHODS: This study was a follow-up of children at 5.5-y of age who participated in a randomized controlled trial evaluating the effect of nutrient-enriched donor milk (commencing at ≥120 mL·kg-1·d-1) or preterm formula fed as a supplement when mother's milk was unavailable. The trial intervention lasted 90 d or until hospital discharge, whichever occurred first. In this follow-up investigation, differences in total body fat percentage determined by using air displacement plethysmography (primary outcome), fat-free mass, skinfold thickness, waist circumference, BMI z scores, and blood pressure] were evaluated using linear regressions. RESULTS: Of 316 surviving infants from the earlier trial, 158 (50%) participated in the current study (53% male). Mean ± SD birth weight and gestational age were 1013 ± 264 g and 27.9 ± 2.5 wk. The median (IQR) intervention period was 67.5 d (52.0-91.0 d). Mean ± SD age and BMI z score at follow-up were 5.7 ± 0.2 y and -0.3 ± 1.2. Supplemental nutrient-enriched donor milk, compared to preterm formula, was not associated with growth, body composition, or blood pressure. In-hospital mother's milk intake was positively associated with height z score at 5.5 y (ß: 0.07; 95% CI: 0.004, 0.1; P = 0.04). CONCLUSIONS: Supplemental nutrient-enriched donor milk and preterm formula during initial hospitalization results in comparable long-term growth and body composition in young children born VLBW. This trial was registered at clinicaltrials.gov as NCT02759809 and at isrctn.com as ISRCTN35317141.

A crucial role for maternal dietary methyl donor intake in epigenetic programming and fetal growth outcomes.

The fetal origins of health and disease framework has identified extremes in fetal growth and birth weight as factors associated with the lifelong generation of chronic diseases such as obesity, diabetes, cardiovascular disease, and hypertension. Maternal nutrition plays a critical role in fetal and placental development, in part by providing the methyl groups required to establish the fetus's genome structure and function, notably through DNA methylation. The goal of this narrative review is to describe the role of maternal dietary methyl donor (methionine, folate, and choline) and cofactor (zinc and vitamins B2, B6, and B12) intake in one-carbon metabolism and DNA methylation in the fetus and placenta, as well as their impacts on fetal growth and lifelong health outcomes, with specific examples in animals and humans. Based on the available evidence, it is concluded that intake of different amounts of dietary methyl donors and cofactors during pregnancy may alter fetal growth and development, thus establishing a major link between early environmental exposure and disease development in the offspring later in life.

Predator avoidance performance of larval fathead minnows (Pimephales promelas) following short-term exposure to estrogen mixtures.

Aquatic organisms exposed to endocrine disrupting compounds (EDCs) at early life-stages may have reduced reproductive fitness via disruption of reproductive and non-reproductive behavioral and physiological pathways. Survival to reproductive age relies upon optimal non-reproductive trait expression, such as adequate predator avoidance responses, which may be impacted through EDC exposure. During a predator-prey confrontation, larval fish use an innate C-start escape behavior to rapidly move away from an approaching threat. We tested the hypotheses that (1) larval fathead minnows exposed to estrogens, a primary class of EDCs, singularly or in mixture, suffer a reduced ability to perform an innate C-start behavior when faced with a threat stimulus; (2) additive effects will cause greater reductions in C-start behavior; and (3) effects will differ among developmental stages. In this study, embryos (post-fertilization until hatching) were exposed for 5 days to environmentally relevant concentrations of estrone (E1), 17beta-estradiol (E2), and 17alpha-ethinylestradiol (EE2) singularly and in mixture. Exposed embryos were allowed to hatch and grow in control well water until 12 days old. Similarly, post-hatch fathead minnows were exposed for 12 days to these compounds. High-speed (1000frames/s) video recordings of escape behavior were collected and transferred to National Institutes of Health Image for frame-by-frame analysis of latency period, escape velocity, and total escape response (combination of latency period and escape velocity). When tested 12 days post-hatch, only E1 adversely affected C-start performance of larvae exposed as embryos. Conversely, larvae exposed for 12 days post-hatch did not exhibit altered escape responses when exposed to E1, while adverse responses were seen in E2 and the estrogen mixture. Ethinylestradiol exposure did not elicit changes in escape behaviors at either developmental stage. The direct impact of reduced C-start performance on survival, and ultimately, reproductive fitness provides an avenue to assess the ecological relevance of exposure in an assay of relatively short duration.

Decreased bone turnover with balanced resorption and formation prevent cortical bone loss during disuse (hibernation) in grizzly bears (Ursus arctos horribilis).

Disuse uncouples bone formation from resorption, leading to increased porosity, decreased bone geometrical properties, and decreased bone mineral content which compromises bone mechanical properties and increases fracture risk. However, black bear bone properties are not adversely affected by aging despite annual periods of disuse (i.e., hibernation), which suggests that bears either prevent bone loss during disuse or lose bone and subsequently recover it at a faster rate than other animals. Here we show decreased cortical bone turnover during hibernation with balanced formation and resorption in grizzly bear femurs. Hibernating grizzly bear femurs were less porous and more mineralized, and did not demonstrate any changes in cortical bone geometry or whole bone mechanical properties compared to active grizzly bear femurs. The activation frequency of intracortical remodeling was 75% lower during hibernation than during periods of physical activity, but the normalized mineral apposition rate was unchanged. These data indicate that bone turnover decreases during hibernation, but osteons continue to refill at normal rates. There were no changes in regional variation of porosity, geometry, or remodeling indices in femurs from hibernating bears, indicating that hibernation did not preferentially affect one region of the cortex. Thus, grizzly bears prevent bone loss during disuse by decreasing bone turnover and maintaining balanced formation and resorption, which preserves bone structure and strength. These results support the idea that bears possess a biological mechanism to prevent disuse osteoporosis.

Black bear femoral geometry and cortical porosity are not adversely affected by ageing despite annual periods of disuse (hibernation).

Disuse (i.e. inactivity) causes bone loss, and a recovery period that is 2-3 times longer than the inactive period is usually required to recover lost bone. However, black bears experience annual disuse (hibernation) and remobilization periods that are approximately equal in length, yet bears maintain or increase cortical bone material properties and whole bone mechanical properties with age. In this study, we investigated the architectural properties of bear femurs to determine whether cortical structure is preserved with age in bears. We showed that cross-sectional geometric properties increase with age, but porosity and resorption cavity density do not change with age in skeletally immature male and female bears. These findings suggest that structural properties substantially contribute to increasing whole bone strength with age in bears, particularly during skeletal maturation. Porosity was not different between skeletally immature and mature bears, and showed minimal regional variations between anatomical quadrants and radial positions that were similar in pattern and magnitude between skeletally immature and mature bears. We also found gender dimorphisms in bear cortical bone properties: females have smaller, less porous bones than males. Our results provide further support for the idea that black bears possess a biological mechanism to prevent disuse osteoporosis.

Parathyroid hormone may maintain bone formation in hibernating black bears (Ursus americanus) to prevent disuse osteoporosis.

Mechanical unloading of bone causes an imbalance in bone formation and resorption leading to bone loss and increased fracture risk. Black bears (Ursus americanus) are inactive for up to six months during hibernation, yet bone mineral content and strength do not decrease with disuse or aging. To test whether hibernating bears have biological mechanisms to prevent disuse osteoporosis, we measured the serum concentrations of hormones and growth factors involved in bone metabolism and correlated them with the serum concentration of a bone formation marker (osteocalcin). Serum was obtained from black bears over a 7-month duration that included periods of activity and inactivity. Both resorption and formation markers increased during hibernation, suggesting high bone turnover occurred during inactivity. However, bone formation appeared to be balanced with bone resorption. The serum concentration of parathyroid hormone (PTH) was higher in the hibernation (P=0.35) and post-hibernation (P=0.006) seasons relative to pre-hibernation levels. Serum leptin was lower (P<0.004) post-hibernation relative to pre-hibernation and hibernation periods. Insulin-like growth factor I (IGF-I) decreased (P<0.0001) during hibernation relative to pre-hibernation and reached its highest value during remobilization. There was no difference (P=0.64) in 25-OH vitamin D between the three seasons. Serum osteocalcin (bone formation marker) was significantly correlated with PTH, but not with leptin, IGF-I or 25-OH vitamin D. Osteocalcin and PTH were positively correlated when samples from all seasons were pooled and when only hibernation samples were considered, raising the possibility that the anabolic actions of PTH help maintain bone formation to prevent disuse osteoporosis. Prostaglandin E(2) (PGE(2)) release from MC3T3 osteoblastic cells was significantly affected by treatment with bear serum from different seasons (i.e. hibernation versus active periods). The seasonal changes in PGE(2) release showed trends similar to the seasonal changes in serum IGF-I. Since both PGE(2) and IGF-I are associated with collagenous bone formation, it is possible that seasonal changes in a circulating factor influence IGF-I levels in vivo in bears and PGE(2) release in osteoblastic cells in vitro. The significant decrease in serum leptin following arousal from hibernation may promote bone formation during remobilization, assuming there is a similar decrease in intracerebroventricular leptin. These findings support the idea that seasonal changes in the concentration of circulating molecules help regulate bone formation activity and may be important for preventing disuse osteoporosis in bears.

Hibernating bears as a model for preventing disuse osteoporosis.

The hibernating bear is an excellent model for disuse osteoporosis in humans because it is a naturally occurring large animal model. Furthermore, bears and humans have similar lower limb skeletal morphology, and bears walk plantigrade like humans. Black bears (Ursus americanus) may not develop disuse osteoporosis during long periods of disuse (i.e. hibernation) because they maintain osteoblastic bone formation during hibernation. As a consequence, bone volume, mineral content, porosity, and strength are not adversely affected by annual periods of disuse. In fact, cortical bone bending strength has been shown to increase with age in hibernating black bears without a significant change in porosity. Other animals require remobilization periods 2-3 times longer than the immobilization period to recover the bone lost during disuse. Our findings support the hypothesis that black bears, which hibernate for as long as 5-7 months annually, have evolved biological mechanisms to mitigate the adverse effects of disuse on bone porosity and strength.