Search

As muscle strength and function decline with age the optimal high-impact physical activity (PA) required for bone remodelling is rarely achievable in older adults. This study aimed to explore the activity profiles of community-dwelling older men and women and to assess the relationship between individual PA profiles and lower limb bone parameters. Participants from the Hertfordshire Cohort Study wore triaxial accelerometers for 7 days and counts of low (0.5-1.0 g), medium (1.0-1.5 g), and high (> 1.5 g) vertical-impact activity were calculated. Two years later, participants underwent a pQCT scan of the tibia (4% and 38% sites) to obtain measures of bone mineral density and bone geometry. Linear regression was used to quantify associations between bone and PA loading profiles adjusting for age, sex, loading category, and BMI. Results are presented as β [95% confidence interval]. Bone and PA data were available for 82 participants. The mean (SD) age at follow-up was 81.4(2.7) years, 41.5% (n = 34) were women. The median low-impact PA count was 5281 (Inter-quartile range (IQR) 2516-12,977), compared with a median of only 189 (IQR 54-593) in medium, and 39 (IQR 9-105) in high-impact counts. Positive associations between high-impact PA and cortical area (mm 2 ), polar SSI (mm 3 ), and total area (mm 2 ) at the 38% slice (6.21 [0.88, 11.54]; 61.94 [25.73, 98.14]; 10.09 [3.18, 16.99], respectively). No significant associations were found at distal tibia. These data suggest that maintaining high (> 1.5 g)-impact activity is difficult for older adults to achieve; however, even small amounts of high-impact PA are positively associated with selected cortical bone parameters 2 years later., (© 2022. The Author(s).)

Objectives: High Bone Mass (HBM) is associated with (a) radiographic knee osteoarthritis (OA), partly mediated by increased BMI, and (b) pelvic enthesophytes and hip osteophytes, suggestive of a bone-forming phenotype. We aimed to establish whether HBM is associated with radiographic features of OA in non-weight-bearing (hand) joints, and whether such OA demonstrates a bone-forming phenotype., Methods: HBM cases (BMD Z-scores≥+3.2) were compared with family controls. A blinded assessor graded all PA hand radiographs for: osteophytes (0-3), joint space narrowing (JSN) (0-3), subchondral sclerosis (0-1), at the index Distal Interphalangeal Joint (DIPJ) and 1st Carpometacarpal Joint (CMCJ), using an established atlas. Analyses used a random effects logistic regression model, adjusting a priori for age and gender. Mediating roles of BMI and bone turnover markers (BTMs) were explored by further adjustment., Results: 314 HBM cases (mean age 61.1years, 74% female) and 183 controls (54.3years, 46% female) were included. Osteophytes (grade≥1) were more common in HBM (DIPJ: 67% vs. 45%, CMCJ: 69% vs. 50%), with adjusted OR [95% CI] 1.82 [1.11, 2.97], p=0.017 and 1.89 [1.19, 3.01], p=0.007 respectively; no differences were seen in JSN. Further adjustment for BMI failed to attenuate ORs for osteophytes in HBM cases vs. controls; DIPJ 1.72 [1.05, 2.83], p=0.032, CMCJ 1.76 [1.00, 3.06], p=0.049. Adjustment for BTMs (concentrations lower amongst HBM cases) did not attenuate ORs., Conclusions: HBM is positively associated with OA in non-weight-bearing joints, independent of BMI. HBM-associated OA is characterised by osteophytes, consistent with a bone-forming phenotype, rather than JSN reflecting cartilage loss. Systemic factors (e.g. genetic architecture) which govern HBM may also increase bone-forming OA risk., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

We previously reported an association between high bone mass (HBM) and a bone-forming phenotype of radiographic hip osteoarthritis (OA). As knee and hip OA have distinct risk factors, in this study we aimed to determine (i) whether HBM is also associated with knee OA, and (ii) whether the HBM knee OA phenotype demonstrates a similar pattern of radiographic features to that observed at the hip. HBM cases (defined by DXA BMD Z-scores) from the UK-based HBM study were compared with unaffected family controls and general population controls from the Chingford and Hertfordshire cohort studies. A single blinded observer graded AP weight-bearing knee radiographs for features of OA (Kellgren-Lawrence score, osteophytes, joint space narrowing (JSN), sclerosis) using an atlas. Analyses used logistic regression, adjusting a priori for age and gender, and additionally for BMI as a potential mediator of the HBM-OA association, using Stata v12. 609 HBM knees in 311 cases (mean age 60.8years, 74% female) and 1937 control knees in 991 controls (63.4years, 81% female) were analysed. The prevalence of radiographic knee OA, defined as Kellgren-Lawrence grade≥2, was increased in cases (31.5% vs. 20.9%), with age and gender adjusted OR [95% CI] 2.38 [1.81, 3.14], p<0.001. The association between HBM and osteophytosis was stronger than that for JSN, both before and after adjustment for BMI which attenuated the ORs for knee OA and osteophytes in cases vs. controls by approximately 50%. Our findings support a positive association between HBM and knee OA. This association was strongest for osteophytes, suggesting HBM confers a general predisposition to a subtype of OA characterised by increased bone formation., (Copyright © 2014. Published by Elsevier Inc.)

Context: The intensity of habitual physical activity (PA) needed to affect skeletal development in childhood is currently unclear., Objective: To examine associations between light PA, moderate PA, and vigorous PA (as assessed by accelerometry), and tibial cortical bone mass (BMC(C)) as measured by peripheral quantitative computed tomography., Design/setting: Cross-sectional analysis based on the Avon Longitudinal Study of Parents and Children., Participants: A total of 1748 boys and girls (mean age 15.5 yr) participated in the study., Outcome Measures: We measured BMC(C), cortical bone mineral density, periosteal circumference, and endosteal circumference by tibial peripheral quantitative computed tomography., Results: Multivariable models, adjusted for height and other activity levels, indicated vigorous PA was positively related to BMC(C) (P = 0.0001). There was little evidence of a relationship with light PA or moderate PA (both P ≥ 0.7). In path analyses, the relationship between vigorous PA and BMC(C) [0.082 (95% confidence interval [CI]: 0.037, 0.128), P = 0.0004] (SD change per doubling of vigorous PA) was minimally attenuated by adjusting for body composition [0.070 (95% CI: 0.026, 0.115), P = 0.002]. In analyses adjusted for body composition, the relationship between vigorous PA and BMC(C) was explained by the periosteal circumference pathway [0.043 (95% CI: 0.004, 0.082), P = 0.03] and the endosteal circumference adjusted for periosteal circumference pathway [0.031 (95% CI: 0.011, 0.050), P = 0.002], while there was little contribution from the cortical bone mineral density pathway (P = 0.3)., Conclusions: Vigorous day-to-day PA is associated with indices of BMC(C) and geometry in adolescents, whereas light or moderate PA has no detectable association. Therefore, promoting PA in childhood is unlikely to benefit skeletal development unless high-impact activities are also increased.

Selective estrogen receptor modulators (SERMs) have been developed as a means of targeting estrogen's protective effect on the skeleton in the treatment of postmenopausal osteoporosis. Although it is well established that SERMs such as tamoxifen inhibit bone resorption in a similar manner to estrogen, whether this agent shares estrogen's stimulatory action on bone formation is currently unclear. To address this question, we compared the effect of treatment for 28 d with 17beta-estradiol (E2; 0.1, 1.0 mg/kg x d) and tamoxifen (0.1, 1.0, or 10 mg/kg x d) on cancellous bone formation at the proximal tibial metaphysis of intact female mice. E2 stimulated the formation of new cancellous bone throughout the metaphysis. A similar response was observed after administration of tamoxifen, the magnitude of which was approximately 50% of that seen after E2. As expected, E2 was found to suppress longitudinal bone growth, but in contrast, this parameter was stimulated by tamoxifen. We conclude that tamoxifen acts as an agonist with respect to estrogen's stimulatory action on bone formation but as an antagonist in terms of estrogen's inhibition of longitudinal growth, suggesting that the protective effect of SERMs on the skeleton is partly mediated by stimulation of osteoblast activity.

Osteoporosis is a common condition in which significant bone loss occurs resulting in an increased risk of sustaining fractures. Several licensed therapies are available to treat this condition, which suffer from several disadvantages including limited efficacy, high cost and poor long-term patient adherence as a consequence of significant side effects and inconvenient methods of administration. A wide range of therapeutic targets have been developed to provide a basis for developing newer therapies which overcome these limitations. These can be subdivided into those that are primarily directed towards inhibiting osteoclast-dependent bone resorption and those that stimulate osteoblastic bone formation. Targets can be grouped as follows: systemic factors such as steroid and peptide hormones; local factors produced in bone involved in osteoblast and osteoclastic regulation; and cellular targets such as cell membrane receptors and attachment proteins, cellular enzymes and nuclear transcription factors. To date, only a small proportion of these targets have yielded novel compounds to have entered clinical trials. However, it is anticipated that these will provide the basis for significant numbers of new therapies for osteoporosis in the foreseeable future.

Although animal studies suggest that there may be major differences between the effects of bisphosphonates and ovarian hormones on skeletal metabolism, whether this also holds for their actions in patients is unknown. To address this question, we compared the effects of 12 weeks treatment with HRT on bone turnover markers in osteopenic postmenopausal women with those of an amino-bisphosphonate. Women within 15 yr of the menopause, with a lumbar and/or femoral neck bone mineral density 1 S.D. below the predicted value, received either oestradiol valerate 2 mg and dydrogesterone 5 mg (E/D; n = 16) or aminohexane bisphosphonate 400 mg (AHBP; n = 9). Urine and serum samples were collected on two separate occasions before starting treatment, and 1, 2, 4, 8 and 12 weeks afterwards. To assess bone resorption, we measured the urinary deoxypyridinoline/creatinine ratio (DPD/crea), while serum alkaline phosphatase (ALP), osteocalcin and C-terminal propeptide of type I collagen (CICP) were analysed to assess bone formation. Repeated measures analysis of variance revealed a highly significant decrease in DPD/crea over the treatment period. Furthermore, this pattern of response differed significantly between the two treatment groups, since DPD/crea was maximally suppressed within 2 weeks of starting AHBP, while E/D showed little decrease until 8 weeks. AHBP was also found to suppress ALP, osteocalcin and CICP more rapidly than E/D, the former reducing these markers by 8 weeks, while E/D caused little inhibition even by 12 weeks. We conclude that, in the doses used in this study, AHBP appears to suppress bone turnover significantly more rapidly than E/D, suggesting that clinically important differences may exist in the effects of bisphosphonates and ovarian hormones on bone metabolism.

We investigated whether androgens, for which the ovaries are the major source in female rats, contribute to the stimulation of cancellous bone formation by ovarian hormones in female rats. Ovariectomized animals were administered 5alpha-dihydrotestosterone (DHT; 10 and 100 microgram/kg) by daily subcutaneous injection for 13 days, after which histomorphometric analysis was performed at the proximal tibial metaphysis. To prevent ovariectomy from stimulating bone turnover, and hence complicating the interpretation of changes in bone formation, animals were also given the resorption inhibitor 3-amino-1-hydroxypropylidene-1-bisphosphonate. We found that ovariectomy markedly suppressed cancellous bone formation, which was partially prevented by DHT (100 microgram/kg). To further address whether androgens contribute to the stimulation of bone formation by ovarian hormones, we treated intact and ovariectomized female rats with the androgen antagonist flutamide (15 mg/kg/day) for 28 days. Whereas flutamide had no effect in ovariectomized rats, it significantly reduced cancellous bone formation in intact animals. We conclude that, in the female rat, androgens contribute under physiological conditions to the stimulation of cancellous bone formation by ovarian hormones.

Although 17 beta-oestradiol (E2) is known to prevent bone loss, prolonged administration of E2 is unable to reverse this in female rats rendered osteopenic by ovariectomy. To determine whether this reflects a failure to replace other components of ovarian function involved in bone metabolism, we compared the effects of administering E2 to osteopenic ovariectomized (ovx) rats with those of ovarian transplantation. Ovariectomy was performed in female rats. After 13 weeks, by which time marked bone loss had occurred, one group of ovx animals received ovaries from donor rats, and, after a delay of 2 weeks to allow oestrus cycles to return, a further group received E2 5 micrograms.kg-1.day-1 for 9 weeks. The dose of E2 was chosen as that which in preliminary studies restored mean serum E2 levels to that of intact female rats. The study was terminated 24 weeks after ovariectomy. Both E2 and ovarian transplantation largely restored indices of oestrogenic exposure in ovx rats to those of sham-ovx animals. Animals receiving ovarian transplants also showed a small increase in serum progesterone and full restoration of serum testosterone. However, while ovarian transplantation also returned indices of cancellous bone metabolism to those of sham-ovx animals, there was little increase in bone volume. Interestingly, exogenous E2 caused a greater increase in cancellous bone volume than ovarian transplantation but also caused more marked suppression of bone formation, as assessed at the end of the study. In conclusion, exogenous E2 and ovarian transplantation exerted distinct effects on skeletal metabolism in osteopenic ovx rats, although the basis for this difference is currently unclear.

Although short-term administration of oestradiol-17 beta (OE2) stimulates cancellous bone formation in the rat, this is replaced by a tendency to suppression after prolonged treatment. Hence, in rats rendered osteopaenic by ovariectomy, OE2 administration fails either to induce a sustained increase in bone formation or to restore bone volume. A possible explanation for this failure is that OE2 also inhibits bone resorption, secondarily suppressing bone formation through coupling mechanisms. We therefore investigated whether the effects of OE2 treatment might be modified by intermittently stimulating bone resorption with retinoic acid (120mg/kg daily) for 4 out of every 20 days. We found, in a preliminary experiment using intact animals, that intermittent retinoic acid reduced cancellous bone volume, consistent with previously documented stimulation of bone resorption by retinoic acid. Rats were then rendered osteopaenic by ovariectomy, and given vehicle, retinoic acid and/or OE2. We found that animals treated with intermittent retinoic acid and OE2 showed a substantial increase in cancellous bone volume compared with ovariectomized animals treated with vehicle, retinoic acid alone or OE2 alone. Therefore, intermittent retinoic acid appears to cause a net increase in bone formation over resorption when given to ovariectomized animals in conjunction with OE2. We conclude that the effects of OE2 on cancellous bone are modified by intermittent treatment with retinoic acid, resulting in a substantial increase in bone volume.

Bone mineral density (BMD) was evaluated by dual energy x ray absorptiometry in 60 adults (33 males, 27 females; aged 50, range 23-76 years) who were growth hormone deficient from various causes for 10.4 (1-31) years. Adult patients who had acquired growth hormone deficiency before completion of puberty had significantly reduced mean (SEM) BMD compared with age matched healthy controls at the lumbar spine: 0.87 (0.09) v 1.20 (0.03) g/cm2, femoral neck: 0.81 (0.06) v 1.08 (0.04) g/cm2, and Ward's triangle: 0.68 (0.07) v 1.04 (0.05) g/cm2. These values were also reduced compared with those of patients who had received human growth hormone during puberty. Untreated growth hormone deficiency when present during puberty results in reduced adult bone density.

Although the effects of low concentrations of 17 beta-estradiol (E2) on bone formation and resorption are well described, little is known of the effects of E2 on bone at concentrations that circulate during pregnancy. We, therefore, investigated the effects of administration of high dose E2 to 3-month-old female Wistar rats on biochemical and histomorphometric indices of bone formation and resorption. Animals receiving exogenous E2 (4 mg/kg.day for 17 days; n = 9) showed a mean serum E2 concentration of 17.5 +/- 2.9 nM, compared with 0.6 +/- 0.2 nM in those receiving vehicle alone (n = 10). The bone formation rate, measured at the proximal tibial metaphysis after the administration of double fluorochrome labels, was greatly increased in the E2 group (13.6 +/- 2.0 x 10(-2) microns3/microns2.day) compared to controls (3.9 +/- 0.9), as was serum alkaline phosphatase (E2, 133.6 +/- 10.1 IU; controls, 87.5 +/- 5.5). This increase in the rate of bone formation was associated with a significant increase in trabecular bone volume. E2 treatment did not affect urinary hydroxyproline excretion or histomorphometric indices of bone resorption. These findings suggest that high concentrations of E2 strongly stimulate the formation of trabecular bone. This may represent an important mechanism by which calcium stores are accumulated during pregnancy in rats, in anticipation of the mineral requirements of lactation.