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Low serum alkaline phosphatase (ALP) was found in 9% of patients attending an osteoporosis clinic, 0.6% of hospital patients, and 2/22 with an atypical femoral fracture. Hypophosphatasia was diagnosed in 3% of osteoporosis clinic patients with low ALP. Low ALP is a screening tool for hypophosphatasia, a condition potentially aggravated by antiresorptive therapy., Introduction: Hypophosphatasia (HPP) is an inherited disorder associated with impaired primary mineralisation of osteoid (osteomalacia). HPP may be misdiagnosed as osteoporosis, a reduction in the volume of normally mineralized bone. Both illnesses may result in fragility fractures, although stress and atypical fractures are more common in HPP. Antiresorptive therapy, first-line treatment for osteoporosis, is relatively contraindicated in HPP. Misdiagnosis and mistreatment can be avoided by recognising a low serum alkaline phosphatase (ALP). Our aim was to determine the prevalence of a low ALP (< 30 IU/L) in patients attending an osteoporosis clinic, in a hospital-wide setting, and in a group of patients with atypical femoral fractures (AFF)., Methods: This was a retrospective study of patients attending an osteoporosis clinic at a tertiary hospital during 8 years (2012-2020). Patients were categorised into those with a transiently low ALP, those with low ALP on ≥ 2 occasions but not the majority of measurements, and those with a persistently low ALP. ALP levels were also assessed in hospital-wide records and a group of patients with AFF., Results: Of 1839 patients attending an osteoporosis clinic, 168 (9%) had ≥ 1 low ALP, 50 (2.7%) had low ALP for ≥ 2 months, and seven (0.4%) had persistently low ALP levels. HPP was diagnosed in five patients, four of whom had persistently low ALP levels. The prevalence of HPP was 0.3% in the osteoporosis clinic and 3% in patients with ≥ 1 low ALP. Low ALP occurred in 0.6% of all hospital patients and 2/22 with AFF., Conclusion: Persistently low ALP in osteoporosis clinic attendees is easy to identify and signals the possibility of hypophosphatasia, a condition that may be mistaken for osteoporosis and incorrectly treated with antiresorptive therapy., (© 2022. Crown.)

In this study of 695 Australian older adults (aged ≥50 years), we found that men and women had a similar trajectory of health-related quality of life (HRQoL) recovery following fragility fracture at any skeletal site. These results provide us with critical knowledge that improves our understanding of health outcomes post-fracture., Introduction: Mortality is higher in men than that in women following a fragility fracture, but it is unclear whether recovery of patient-reported outcomes such as health-related quality of life (HRQoL) differs between sexes. This study aimed to identify sex differences in HRQoL recovery 12 months post-fracture., Methods: Data were from the Australian arm of the International Costs and Utilities Related to Osteoporotic Fractures Study (AusICUROS). Participants recruited to AusICUROS were adults aged ≥50 years who sustained a fragility fracture. HRQoL was measured using the EQ-5D-3L at three time-points post-fracture: within 2 weeks (including pre-fracture recall) and at 4 and 12 months. Multivariate logistic regression analyses were undertaken, adjusting for confounders including age, education, income, and healthcare utilization post-fracture., Results: Overall, 695 AusICUROS participants (536 women, 77.1%) were eligible for analysis with fractures at the hip (n = 150), distal forearm (n = 261), vertebrae (n = 61), humerus (n = 52), and other skeletal sites (n = 171). At the time of fracture, men were younger, reported a higher income, and were more likely to be employed, compared with women. For all fracture sites combined, there were no differences between men and women in recovery to pre-fracture HRQoL at 12-month follow-up (adjusted OR = 1.09; 95% CI: 0.75-1.61). When stratified by fracture site, no significant sex differences were seen for hip (OR = 1.02; 95% CI: 0.42-2.52), distal forearm (OR = 1.60; 95% CI: 0.68-3.78), vertebral (OR = 2.28; 95% CI: 0.61-8.48), humeral (OR = 1.62; 95% CI: 0.16-9.99), and other fractures (OR = 1.00; 95% CI: 0.44-2.26)., Conclusion: Community-dwelling men and women who survived the 12 months following fragility fracture had a similar trajectory of HRQoL recovery at any skeletal site., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Two women presenting with fragility fractures during lactation had bone mineral density (BMD) reduced more greatly than usually associated with lactation. The first woman was 29 years old with a BMD T-score of - 3.2 SD at the spine and- 2.0 SD at the femoral neck. The second woman was 35 years old with a BMD T-score of - 4.5 SD at the spine and - 2.8 SD at the femoral neck. Both women had increased cortical porosity and reduced trabecular density. Investigation identified an elevated serum tryptase, and marrow biopsy confirmed the diagnosis of mastocytosis. Lactation causes bone loss, but the occurrence of fractures in the setting of severe deficits in BMD and microstructural deterioration signals the need to consider additional causes of bone loss.

Unlabelled: We tested whether GPRC6A, the putative receptor of undercarboxylated osteocalcin (ucOC), is present in mouse muscle and whether ucOC increases insulin sensitivity following ex vivo muscle contraction. GPPRC6A is expressed in mouse muscle and in the mouse myotubes from a cell line. ucOC potentiated the effect of ex vivo contraction on insulin sensitivity., Introduction: Acute exercise increases skeletal muscle insulin sensitivity. In humans, exercise increases circulating ucOC, a hormone that increases insulin sensitivity in rodents. We tested whether GPRC6A, the putative receptor of ucOC, is present in mouse muscle and whether recombinant ucOC increases insulin sensitivity in both C2C12 myotubes and whole mouse muscle following ex vivo muscle contraction., Methods: Glucose uptake was examined in C2C12 myotubes that express GPRC6A following treatment with insulin alone or with insulin and increasing ucOC concentrations (0.3, 3, 10 and 30 ng/ml). In addition, glucose uptake, phosphorylated (p-)AKT and p-AS160 were examined ex vivo in extensor digitorum longus (EDL) dissected from C57BL/6J wild-type mice, at rest, following insulin alone, after muscle contraction followed by insulin and after muscle contraction followed by recombinant ucOC then insulin exposure., Results: We observed protein expression of the likely receptor for ucOC, GPRC6A, in whole muscle sections and differentiated mouse myotubes. We observed reduced GPRC6A expression following siRNA transfection. ucOC significantly increased insulin-stimulated glucose uptake dose-dependently up to 10 ng/ml, in differentiated mouse C2C12 myotubes. Insulin increased EDL glucose uptake (∼30 %, p < 0.05) and p-AKT and p-AKT/AKT compared with rest (all p < 0.05). Contraction prior to insulin increased muscle glucose uptake (∼25 %, p < 0.05), p-AKT, p-AKT/AKT, p-AS160 and p-AS160/AS160 compared with contraction alone (all p < 0.05). ucOC after contraction increased insulin-stimulated muscle glucose uptake (∼12 % p < 0.05) and p-AS160 (<0.05) more than contraction plus insulin alone but without effect on p-AKT. In the absence of insulin and/or of contraction, ucOC had no significant effect on muscle glucose uptake., Conclusions: GPRC6A, the likely receptor of osteocalcin (OC), is expressed in mouse muscle. ucOC treatment augments insulin-stimulated skeletal muscle glucose uptake in C2C12 myotubes and following ex vivo muscle contraction. ucOC may partly account for the insulin sensitizing effect of exercise.

We report that a postmenopausal woman with osteoporosis developed bilateral incomplete atypical femoral fractures (AFFs) after seven years of bisphosphonate therapy. Cessation of the bisphosphonate and treatment with teriparatide was associated with near complete radiological resolution of the AFFs. After 12 months without treatment, denosumab was commenced to prevent structural deterioration. Six months later she developed recurrent bilateral AFFs. This case highlights the management dilemma in patients with ongoing bone loss but prone to stress fractures associated with antiresorptive therapy. Stopping the antiresorptive is recommended but structural decay will recur predisposing to fragility fractures. If the antiresorptive is continued, bone material composition will be further compromised predisposing to atypical fractures. Teriparatide may assist healing of stress fractures and improvement in bone matrix composition. Later antiresosrptive therapy to preserve bone microstructure may compromise material composition.

Unlabelled: We tested whether cortical porosity of the proximal femur measured using StrAx1.0 software provides additional information to areal bone mineral density (aBMD) or Fracture Risk Assessment Tool (FRAX) in differentiating women with and without fracture. Porosity was associated with fracture independent of aBMD and FRAX and identified additional women with fractures than by osteoporosis or FRAX thresholds., Introduction: Neither aBMD nor the FRAX captures cortical porosity, a major determinant of bone strength. We therefore tested whether combining porosity with aBMD or FRAX improves identification of women with fractures., Methods: We quantified femoral neck (FN) aBMD using dual-energy X-ray absorptiometry, FRAX score, and femoral subtrochanteric cortical porosity using StrAx1.0 software in 211 postmenopausal women aged 54-94 years with nonvertebral fractures and 232 controls in Tromsø, Norway. Odds ratios (ORs) were calculated using logistic regression analysis., Results: Women with fractures had lower FN aBMD, higher FRAX score, and higher cortical porosity than controls (all p < 0.001). Each standard deviation higher porosity was associated with fracture independent of FN aBMD (OR 1.39; 95% confidence interval 1.11-1.74) and FRAX score (OR 1.58; 1.27-1.97) in all women combined. Porosity was also associated with fracture independent of FRAX score in subgroups with normal FN aBMD (OR 1.88; 1.21-2.94), osteopenia (OR 1.40; 1.06-1.85), but not significantly in those with osteoporosis (OR 1.48; 0.68-3.23). Of the 211 fracture cases, only 18 women (9%) were identified using FN aBMD T-score < -2.5, 45 women (21%) using FRAX threshold >20%, whereas porosity >80th percentile identified 61 women (29%). Porosity identified 26% additional women with fractures than identified by the osteoporosis threshold and 21% additional women with fractures than by this FRAX threshold., Conclusions: Cortical porosity is a risk factor for fracture independent of aBMD and FRAX and improves identification of women with fracture.

Unlabelled: We investigated change in health-related quality of life due to fracture in Australian adults aged over 50 years. Fractures reduce quality of life with the loss sustained at least over 12 months. At a population level, the loss was equivalent to 65 days in full health per fracture., Purpose: We aimed to quantify the change in health-related quality of life (HRQoL) that occurred as a consequence of a fracture using the EQ-5D-3 L questionnaire., Methods: Adults aged ≥50 years with a low to moderate energy fracture were recruited from eight study centres across Australia. This prospective study included an 18-month follow-up of participants recruited within 2 weeks of a fracture (hip, wrist, humerus, vertebral and ankle). Information collected at baseline and 4, 12 and 18 months included characteristics of participants such as income level, education and prior fracture status. At 12 months post-fracture, the cumulative loss of quality of life was estimated using multivariate regression analysis to identify the predictors of HRQoL loss., Results: Mean HRQoL for all participants before fracture was 0.86, with wrist fracture having the highest pre-fracture HRQoL (0.90), while vertebral fracture had the lowest (0.80). HRQoL declined to 0.42 in the immediate post-fracture period. Only participants with a wrist, humerus or ankle fracture returned to their pre-fracture HRQoL after 18 months. An increased loss of HRQoL over 12 months was associated with HRQoL prior to the fracture, hospitalisation, education and fracture site. The multiple regression explained 30 % of the variation in the cumulative HRQoL loss at 12 months post-fracture for all fractures., Conclusion: Low to moderate energy fractures reduce HRQoL, and this loss is sustained for at least 12 months or, in the case of hip and spine fractures, at least 18 months. At a population level, this represents an average loss of 65 days in full health per fragility fracture. This significant burden reinforces the need for cost-effective fracture prevention strategies.

Unlabelled: In this longitudinal case-control study, acute fracture was associated with low serum testosterone, which was transient in 43% of men. While assessment of gonadal status is part of the assessment of bone fragility, measurement of testosterone in the early period after fracture may overestimate the prevalence of androgen deficiency., Introduction: Measurement of circulating testosterone is recommended in the evaluation of bone fragility in men. Since acute illness can transiently decrease circulating testosterone, we quantified the association of acute fracture and serum testosterone levels., Methods: A case-control study was conducted involving 240 men with a radiologically confirmed minimal trauma fracture presenting to a tertiary referral hospital and 89 age-matched men without a history of minimal trauma fracture serving as controls. Follow-up testosterone levels 6 months after baseline were available for 98 cases and 27 controls. Results were expressed as the median and interquartile (IQR) range., Results: Compared to controls, cases had lower total testosterone [TT, 7.2 (3.5, 10.8) vs 13.6 (10.9, 17.1) nmol/L, p < 0.001]. The 143 cases treated as inpatients had lower testosterone levels than the 97 cases treated as outpatients [TT 4.7 (2.3, 8.1) vs 10.3 (7.5, 12.7) nmol/L, p < 0.001]. Group differences in calculated free testosterone (cFT) were comparable to the group differences in TT. At follow-up, in 98 cases, median TT increased from 6.5 nmol/L (3.2, 8.5) to 9.6 nmol/L (6.9, 12.0) p < 0.0001, and SHBG remained unchanged. Of cases with low testosterone, 43% with TT <10 nmol/L and/or cFT <230 pmol/L at presentation were reclassified as androgen sufficient at follow-up. TT was unchanged in the controls., Conclusions: Low testosterone levels in men presenting with an acute fracture may, at least in part, be due to an acute, fracture-associated, stress response. To avoid over diagnosis, evaluation for testosterone deficiency should be deferred until recovery from the acute event.

Unlabelled: Bone remodelling is inhibited by high repetitive loading. However, in subchondral bone of racehorses in training, eroded surface doubled in association with fatigue fracture and there was greater surrounding trabecular bone volume suggesting trabecular modelling unloads the bone focally, allowing damage repair by remodelling., Introduction: Remodelling replaces damaged bone with new bone but is suppressed during high magnitude repetitive loading when damage is most likely. However, in cortical bone of racehorses, at sites of fatigue fracture, focal porosity, consistent with remodelling, is observed in proportion to the extent of surrounding callus. Focal areas of porosity are also observed at sites of fatigue damage in subchondral bone. We hypothesised that fatigued subchondral bone, like damaged cortical bone, is remodelled focally in proportion to the modelling of surrounding trabecular bone., Methods: Eroded and mineralizing surfaces and bone area were measured using backscattered scanning electron microscopy of post-mortem specimens of the distal third metacarpal bone in 11 racehorses with condylar fractures (cases) and eight racehorses in training without fractures (controls)., Results: Cases had a two-fold greater eroded surface per unit area at the fracture site than controls (0.81 ± 0.10 vs. 0.40 ± 0.12 mm(-1), P = 0.021) but not at an adjacent site (0.22 ± 0.09 vs. 0.30 ± 0.11 mm(-1), P = 0.59). Area fraction of surrounding trabecular bone was higher in cases than controls (81 ± 2 vs. 72 ± 2 %, P = 0.0020) and the eroded surface at the fracture site correlated with the surrounding trabecular area (adjusted R (2) = 0.63, P = 0.0010)., Conclusion: In conclusion, exercise-induced inhibition of remodelling is offset at sites of fatigue fracture. Modelling of trabecular bone may contribute to unloading these regions, allowing repair by remodelling.

Unlabelled: Guidelines concerning the definition of failure of therapies used to reduce the risk of fracture are provided., Introduction: This study aims to provide guidelines concerning the definition of failure of therapies used to reduce the risk of fracture., Methods: A working group of the Committee of Scientific Advisors of the International Osteoporosis Foundation was convened to define outcome variables that may assist clinicians in decision making., Results: In the face of limited evidence, failure of treatment may be inferred when two or more incident fractures have occurred during treatment, when serial measurements of bone remodelling markers are not suppressed by anti-resorptive therapy and where bone mineral density continues to decrease., Conclusion: The provision of pragmatic criteria to define failure to respond to treatment provides an unmet clinical need and may stimulate research into an important issue.

Unlabelled: Sunlight deprivation results in vitamin D deficiency but serum vitamin D levels can be maintained above 50 nmol/L when supplemented with 50,000 IU at least every alternate month., Introduction: Antarctic expeditioners are exposed to prolonged sunlight deprivation resulting in vitamin D deficiency. We hypothesised that monthly dosing of 50,000 IU vitamin D (~1,600 IU daily) will increase serum 25-hydroxyvitamin D (25(OH)D), suppress parathyroid hormone (PTH) and improve bone mineral density (BMD), 50,000 IU alternate months (~800 IU daily) will maintain these measures, while a single 50,000 IU dose pre-departure (~1,00 IU daily) will not be protective., Methods: This was a randomised double-blind study involving 110 healthy adults: 91 males, mean age 41 years (range 24-65 years) working in Antarctica for up to 12 months, who we administered 50,000 IU vitamin D3 monthly, alternate months or a single dose pre-departure. Serum 25(OH)D, PTH, osteocalcin, CTx and calcium were assessed at baseline, mid- and end of expedition. Proximal femur and lumbar spine BMD were assessed pre- and post-expedition., Results: Baseline 25(OH)D was 59 ± 14 nmol/L. By mid-expedition, 25(OH)D increased by 7 nmol/L in those supplemented monthly (p < 0.05) and remained unchanged in those supplemented in alternate months. In those given a single dose pre-departure, 25(OH)D decreased by 8 nmol/L (p < 0.05) and PTH increased by 27% (p < 0.09). Serum osteocalcin increased by ~22% in all groups but BMD remained unchanged. If serum 25(OH)D was >50 nmol/L at baseline, 25(OH)D was maintained above this level with all regimens. If 25(OH)D was <50 nmol/L at baseline, monthly or alternate month regimens were needed to achieve levels >50 nmol/L, the single pre-departure dose was ineffective., Conclusion: During sunlight deprivation of up to 12 months, serum 25(OH)D levels can be maintained above 50 nmol/L when expeditioners are provided with 50,000 I U at least every alternate month.

Chinese have similar vertebral fracture prevalence but lower incidence of hip and distal forearm fractures than in Caucasians. The underlying structural and biomechanical basis of racial differences in bone fragility is still largely undefined but Chinese assemble their smaller appendicular skeleton with thicker cortices and trabeculae compared with Caucasians. Vertebral fracture prevalence is similar by race, but the incidence of hip and distal forearm fractures is lower in Chinese than in Caucasians. This racial dimorphism cannot be explained by differences in areal bone mineral density (aBMD) as aBMD is lower in Chinese mainly due to their smaller size. The underlying structural and biomechanical basis of racial differences in bone fragility is still largely undefined but Chinese assemble their smaller appendicular skeleton with more mineralised bone matrix within it; the cortices are thicker and perhaps less porous while trabeculae are fewer but thicker and more connected. This configuration produces a bone with a lower surface/volume ratio, which in turn reduces the surface available for remodelling to occur upon so that the lower surface/volume ratio may make the bone less exposed to remodelling and the thicker cortices and trabeculae less vulnerable to remodelling when it does occur during advancing age. However, prospective studies are needed to define racial differences at the age of onset, rate of bone loss from the intracortical, endocortical and trabecular components of the endosteal envelope and bone formation upon the periosteal envelope; notions of bone 'loss' are derived mainly from cross-sectional studies. Studies of the site- and surface-specific changes in bone modelling and remodelling are needed to better define racial differences in bone fragility in old age.

Unlabelled: We examined prevalent and recent vertebral fractures in 1 year as predictors of new vertebral fractures over subsequent 2 years using data from RCT placebo patients. We found that prevalent and recent vertebral fractures strongly and independently predicted subsequent vertebral fractures including those which were severe., Introduction: While several studies have shown that prevalent vertebral fractures (pVFx) increase the risk of new vertebral fractures (VFx), the impact of recent vertebral fractures on future fractures is less studied., Methods: Data from the placebo arm of the HORIZON Pivotal Fracture Trial, an international trial of zoledronic acid in postmenopausal, osteoporotic women between 65 and 85 years, were used. We included the subset of 2677 women with annual spinal radiographs to study the impact of vertebral fractures in year 1 (Y1 VF) on those occurring in years 2 and 3 using morphometric and semiquantitative (SQ) criteria. In addition, a subset of severe VFx was defined using SQ criteria. Logistic regression examined the impact of pVFx and Y1 VF on all incident VFx and on severe incident VFx., Results: Two hundred fourty-five (9.1%) women sustained a new VFx in years 2-3. VFx risk in years 2-3 was 3.9% in those without pVFx or VFy1 and 29.8% in those with both risk factors. Both pVF and VFy1 remained independent predictors for future VF when they were both entered into a logistic regression model (odds ratio (OR) = 3.3; 95% confidence interval (CI), 2.3-4.7; OR = 3.7, 95% CI, 2.3, 5.8, respectively). ORs were similar after adjustment. Of the total number of women, 4.1% had severe VFx. PVFx and Y1 VF were also significant predictors of severe VFx; however, Y1 VF appeared more strongly predictive of severe VFx., Conclusions: Prevalent and incident vertebral fractures are highly predictive of subsequent new and severe vertebral fractures. Women with both of these risk factors are likely to benefit from anti-osteoporosis treatment.

Unlabelled: The consensus views on osteoporosis in men are reported., Introduction: A workshop was convened within a meeting on osteoporosis in men to identify areas of consensus amongst the panel (the authors) and the participants of the meeting., Methods: A public debate with an expert panel on preselected topics was conducted., Results and Conclusions: Consensus views were reached on diagnostic criteria and several aspects on the pathophysiology and treatment of osteoporosis in men.

Summary: The purpose of this study was to examine if the reduction in glucose post-exercise is mediated by undercarboxylated osteocalcin (unOC). Obese men were randomly assigned to do aerobic or power exercises. The change in unOC levels was correlated with the change in glucose levels post-exercise. The reduction in glucose post-acute exercise may be partly related to increased unOC., Introduction: Osteocalcin (OC) in its undercarboxylated (unOC) form may contribute to the regulation of glucose homeostasis. As exercise reduces serum glucose and improves insulin sensitivity in obese individuals and individuals with type 2 diabetes (T2DM), we hypothesised that this benefit was partly mediated by unOC., Methods: Twenty-eight middle-aged (52.4 ± 1.2 years, mean ± SEM), obese (BMI = 32.1 ± 0.9 kg m(-2)) men were randomly assigned to do either 45 min of aerobic (cycling at 75% of VO(2peak)) or power (leg press at 75% of one repetition maximum plus jumping sequence) exercises. Blood samples were taken at baseline and up to 2 h post-exercise., Results: At baseline, unOC was negatively correlated with glucose levels (r = -0.53, p = 0.003) and glycosylated haemoglobin (HbA1c) (r = -0.37, p = 0.035). Both aerobic and power exercises reduced serum glucose (from 7.4 ± 1.2 to 5.1 ± 0.5 mmol L(-1), p = 0.01 and 8.5 ± 1.2 to 6.0 ± 0.6 mmol L(-1), p = 0.01, respectively). Aerobic exercise significantly increased OC, unOC and high-molecular-weight adiponectin, while power exercise had a limited effect on OC and unOC. Overall, those with higher baseline glucose and HbA1c had greater reductions in glucose levels after exercise (r = -0.46, p = 0.013 and r = -0.43, p = 0.019, respectively). In a sub-group of obese people with T2DM, the percentage change in unOC levels was correlated with the percentage change in glucose levels post-exercise (r = -0.51, p = 0.038)., Conclusions: This study reports that the reduction in serum glucose post-acute exercise (especially aerobic exercise) may be partly related to increased unOC.

Unlabelled: Serum 25(OH)D levels decline without sunlight exposure. We studied 120 expeditioners to Antarctica to determine the skeletal and hormonal responses to sunlight deprivation. With emerging vitamin D insufficiency, serum calcium decreased, PTH increased, and bone loss at the proximal femur was observed. Baseline serum 25(OH)D levels >100 nmol/L prevented vitamin D insufficiency., Introduction: Vitamin D stores deplete without adequate sunlight exposure unless supplementation is provided. We studied 120 healthy adults who spent a year in Antarctica as a model for sunlight deprivation to define the timing and magnitude of the skeletal and hormonal responses to emerging vitamin D insufficiency., Methods: Fasting blood samples were assessed at baseline, 6 and 12 months for serum 25-hydroxyvitamin D (25(OH)D), osteocalcin (OC), bone formation (P1NP) and resorption (CTx), PTH and calcium. Lumbar spine and proximal femur BMD was measured using DXA. Differences over time were determined using repeated measures ANOVA. Percent changes were expressed as (Delta value/(value A + value B)/2) x 100. Relationships between outcome measures were determined using Spearman's correlations., Results: Vitamin D insufficiency (<50 nmol/L) was observed in 85% of expeditioners by 6 months when serum calcium decreased and PTH increased (p < 0.01). By 12 months, OC increased by 7.4 +/- 3.0% (p < 0.05), and BMD decreased by 1.0 +/- 2.0% at the total proximal femur (p < 0.05). For those with vitamin D sufficiency at baseline (>50 nmol/L), sunlight deprivation produced vitamin D insufficiency within 4 months unless baseline values were >100 nmol/L., Conclusion: Supplementation may be necessary for expeditioners with limited access to UV light.

Introduction: Bone modeling and remodeling is the final common pathway expressing all genetic and environmental factors that influence the attainment and maintenance of bone's material and structural strength. Modeling and remodeling require a surface, and during growth this cellular machinery fashions bone's external size, shape, and internal architecture by depositing bone on, and removing bone from, both its periosteal (external) and endosteal (internal) envelopes. Bone is distributed and redistributed to achieve strength commensurate with its loading requirements., Methods: Advancing age is associated with: (1) a reduction in the volume of bone resorbed by each basic multicellular unit (BMU); (2) an even greater reduction in the volume of bone formed by each BMU so that each remodeling event, whether adaptive or reparative, removes bone from the bone; (3) increased remodeling (number of BMUs) on the three (endocortical, intracortical, and trabecular) components of its endosteal envelope in midlife in women and late in life in both sexes; and (4) reduced bone formation on the periosteal envelope. The net effect is cortical thinning, increased intracortical porosity, trabecular thinning, and loss of connectivity., Results: While remodeling intensity on an envelope determines structure (e.g., trabecular perforations), the surface area of the envelope determines remodeling intensity, and, so, structure. High remodeling on trabecular surfaces decreases as trabeculae (with their surface) are lost. Conversely, remodeling on the endocortical and intracortical envelopes increases their surface area, so remodeling intensity increases and bone loss becomes predominantly cortical., Conclusions: Understanding bone structural strength and its decay and the effects of genetic factors, exercise, nutrition, and drug therapy on bone requires thinking outside and inside these envelopes; their absolute and relative movements during growth and aging determine bone structure and its strength.

Introduction: In a case control study, we report that women and men with hip fractures have a longer moment arm of the force applied on the proximal femur during a sideways fall, a structural feature that may contribute to fracture risk. The impact load and its direction during a sideways fall onto the greater trochanter are partly determined by the geometry of the proximal femur. We hypothesized that the hip geometry in elderly with hip fractures produces a greater impact on the hip during a sideways fall., Methods: We studied 41 female (77.2 +/- 9.9 years) and 22 male (76.2 +/- 12.1 years) patients with hip fractures and 40 female (85.7 +/- 6.0 years) and 17 male (84.3 +/- 10.1 years) controls. Hip geometry was analyzed on the nonfracture hip in patients and left hip in controls using dual-energy X-ray absorptiometry., Results: There was no difference in areal bone mineral density (aBMD), hip axis length, femoral neck axis length, or neck-shaft angle between cases and controls. However, the moment arm of the force on the hip during a sideways fall was 7.3% and 9.5% longer resulting in 5.6% and 9.1% greater moment in such a fall in female and male cases relative to their respective controls independent of height and weight (all p < 0.056). In multivariate logistic regression analysis, only the moment arm length in a sideways fall was associated with increased risk of hip fracture in females (odds ratio = 1.91, 95%CI: 1.14-3.20 for each SD increase in moment arm length of sideways fall, p = 0.02) and males (odds ratio = 2.69, 95% CI, 1.19-6.09, p = 0.01)., Conclusions: A longer moment arm in the sideways fall increases the resultant force applied to the hip predisposing to hip fracture.

Treatment aimed at preventing fractures should be stopped if evidence of continued antifracture efficacy is lacking, if continued treatment increases bone fragility by adversely affecting matrix properties, and if stopping does not increased bone fragility. Credible evidence of antifracture efficacy beyond 5 years is lacking because of attrition of the cohort originally allocated to treatment or placebo and lack of controls. Prolonged suppression of remodeling is associated with accumulation of microdamage, advanced glycation products and increased tissue mineral density in animal studies but the structural benefits appear to out weight these adverse effects. Atypical minimal trauma subtrochanteric fractures are associated with prolonged treatment in human subjects but these are exceedingly rare. Stopping treatment does result in the reemergence of remodeling, rapidly with some drugs, more slowly with others while fracture rates are increased in poor compliers to treatment. Thus, within the constraints of limited evidence, I infer that stopping therapy is more likely to do net harm than continuing therapy - treatment should be continued in the majority of individuals.

Unlabelled: Dietary calcium deficiency may increase fracture risk. In girls, 29.4% of fracture cases and 11.8% of controls without fracture had a history of milk-free diet. The odds ratio (OR) for fracture with a milk-free diet in girls was 4.6, p < 0.01. In boys, 23% of cases and 19% of controls had a history of a milk-free diet; OR = 1.3, NS). A milk-free diet due to cow's milk allergy is associated with increased fracture risk in girls., Introduction: An intake of calcium below the reference daily intake (RDI) of 800-1200 mg/day during growth is thought to increase fracture risk even though convincing evidence for this view is scarce. The paucity of evidence may be partly due to many trial participants being calcium replete. Children and adolescents with cow's milk allergy (CMA) avoid milk and have a calcium intake below the RDI. The aim of this study was to examine the association between consumption of a milk-free diet and fracture risk., Methods: In this case-control study conducted in Poland, 57 boys and 34 girls aged 2.5-20 years with fractures (cases) were randomly matched by age and sex with 171 boys and 102 girls without fractures (controls). Weight and height were examined using standard methods. Bone mineral density (BMD) and body composition were measured using dual-energy X-ray absorptiometry. Conditional logistic regression and Bayesian analyses were used to determine the proportion of the fracture risk attributable to a milk-free diet., Results: In girls, 29.4% of cases and 11.8% of controls had a history of milk-free diet producing an odds ratio (OR) for fracture associated with a milk-free diet of 4.6 (95% confidence interval [CI]: 1.4-15.5, p < 0.01). In boys, 23% of cases and 19% of controls had a history of a milk-free diet; OR = 1.3 (95% CI: 0.6-2.7, NS). If the prevalence of CMA in the population is 5%, only 6.7% of the fractures occurring are attributable to CMA and the associated nutritional deficit., Conclusions: Cow's milk allergy is associated with increased fracture risk in girls. Whether this association is due to the illness, calcium deficit or a deficit in other milk nutrients is uncertain. These data suggest that the contribution of milk-free diet to fracture liability among children and adolescents is modest.

About 50% of patients fail to comply or persist with anti-osteoporosis treatment regimens within 1 year. Poor compliance is associated with higher fracture rates. Causes of poor compliance are unknown. As it is not possible to predict poor compliance, close monitoring of compliance is needed. Despite evidence supporting the anti-fracture efficacy of several pharmacological agents, approximately 50% of patients do not follow their prescribed treatment regimen and/or discontinue treatment within 1 year. Poor compliance is associated with higher fracture rates and increased morbidity, mortality and cost. However, as poor compliance, even to placebo, is associated with adverse outcomes, the higher morbidity appears to be only partly the result of lack of treatment: as yet, undefined characteristics place poor compliers at higher risk of morbidity and mortality. Only a small proportion (e.g., 6%) of the variability in compliance is explained by putative causal factors such as older age, co-morbidity or greater number of medications. Regimens with longer dosing intervals, such as weekly dosing, improve compliance, persistence and outcomes, but only modestly. As it is not possible to predict poor compliance, close monitoring of compliance should be an obligatory duty in clinical care. How this is best achieved has yet to be established, but poor persistence occurs as early as 3 months of starting treatment, indicating the need for early monitoring.

Introduction and Hypothesis: The spinal curvature irregularity index (SCII) is a quantitative measure of the irregularity of the spinal curvature. We evaluated the predictive ability of SCII to identify subjects with vertebral fractures (VF)., Methods: Vertebral heights were measured by quantitative vertebral morphometry in 461 Lebanese women 20-89 years of age and VFs were ascertained by the grade 1 Eastell method. SCII scores were log-transformed and expressed as Z-SCII, the number of standard deviations above or below the mean ln(SCII) of young patients without VF. Univariate and multivariate binary logistic regression models were used to identify clinical predictors of VF., Results: Women with a higher SCII were more likely to have prevalent VF. A higher SCII was associated with a greater prevalence of VF within each category of femoral neck BMD (normal, osteopenia, osteoporosis). In univariate analysis, predictors of VF included Z-SCII (odds ratio, OR: 2.21, 95% CI: 1.80-2.71) and femoral neck T-score (OR: 1.35, 95% CI: 1.12-1.63). In multivariate analysis, predictors of VF were: Z-SCII (OR: 1.54, 95% CI: 1.02-2.32), femoral neck T-score (OR: 1.41, 95% CI: 1.11-1.78) and age(3) (OR: 1.40, 95% CI 1.10-1.82). At a cutoff SCII of 9.5%, the sensitivity and specificity of SCII for VF were 71 and 64% respectively, and higher SCII cutoffs identified VFs with greater specificity., Conclusion: The SCII is a robust, simple and independent indicator of the presence of VFs.

Introduction and Hypothesis: Calcium supplementation enhances bone mass accrual during administration, with a sustained benefit observed using milk-based calcium but not calcium salts. We tested the hypothesis that calcium from milk minerals but not calcium carbonate will be sustained after supplementation was discontinued., Methods: Ninety-nine pre-pubertal boys and girls aged 5-11 years were followed for 12 months after being randomized to receive 800 mg/day of calcium from milk minerals (MM) or calcium carbonate (CC), or a placebo (Pla) in a 10-month double blind study. Total body and regional BMC, and femoral shaft bone dimensions were measured using dual energy x-ray absorptiometry. Group differences were determined using ANCOVA., Results: In the intention to treat analysis of the entire sample, no group differences were observed in increments in BMC or bone dimensions during or after supplementation. In those children who remained pre-pubertal, greater gains in pelvis BMC in the milk mineral group than controls were sustained (37.9 versus 29.3% respectively, p<0.02)., Conclusion: In healthy children consuming about 800 mg calcium daily, calcium supplementation with milk minerals or calcium carbonate does not appear to be produce biologically meaningful benefits to skeletal health. A benefit of calcium supplementation in pre-pubertal was evident, but inconclusive, with the biological significance of the effect of calcium supplementation at the pelvis, and the longevity of this effect to be determined.

Introduction: Oral glucocorticoid therapy reduces bone mineral density (BMD) and increases fracture risk. It is uncertain whether inhaled glucocorticoids, the most commonly used long-term therapy for asthma, have a similar effect. If bone loss does occur, it is unclear whether this is preventable by calcitriol. Patients with asthma receiving inhalational plus intermittent oral glucocorticoids lose bone, and treatment with 0.5 microg/day of calcitriol will prevent bone loss., Methods: A 2-year randomized double-blind placebo-controlled trial. One hundred eight patients with asthma were stratified by gender, age, and inhaled glucocorticoid dose and treated with calcitriol (n=55) or placebo (n=53). There were 41 men (mean age 53.2+/-1.7 years) and 67 women (mean age 49.1+/-1 years) with moderate to severe asthma (requiring >/=800 microg/day of beclomethasone dipropionate or equivalent maintenance therapy). BMD values at the lumbar spine (LS) and femoral neck (FN) were measured at baseline and at 6, 12, and 24 months using dual x-ray absorptiometry., Results: Changes in LS and FN BMD. Bone loss occurred in both groups at the FN (both p<0.03) and at the LS in the calcitriol (p<0.001), but not the control, group. Bone loss was not less in the calcitriol group at either site., Conclusion: Patients with asthma receiving inhalational plus intermittent short courses of oral glucocorticoids lose bone. Calcitriol is unlikely to be appropriate therapy against this bone loss.

In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced the risk of vertebral fracture. However, a systematic analysis of the anti-vertebral fracture efficacy of raloxifene, which includes the results of newly reported studies, has not been performed. A meta-analysis was carried out using all randomized, double-blind, placebo-controlled trials to determine whether the reduction in the risk for vertebral fracture, reported with raloxifene, was consistent among studies, and to define more accurately the point estimate of the odds ratio. Three prevention studies, two arms of the MORE trial, and three additional treatment studies in which fracture data were available from prospectively scheduled spinal radiographs were included in the analysis. A systematic review of the literature (MedLine, EMBASE) confirmed that no studies with raloxifene had been excluded from this analysis. The effects of raloxifene 60 mg/day (RLX60) and 120 mg/day pooled with 150 mg/day (RLX120/150) were analyzed by intention to treat. There was no significant heterogeneity among the studies included in the meta-analysis. Odds ratio estimates (95% CI) were 0.60 (0.49, 0.74) for RLX60 and 0.51 (0.41, 0.64) for RLX120/150. From these data we infer that raloxifene consistently reduces the risk of vertebral fracture in postmenopausal women.

Introduction: Osteoporosis is associated with increased risk for fracture. However, most postmenopausal women have bone mineral density (BMD) within the normal or osteopenic range. The aim of this study was to determine the proportion of the population burden of fragility fractures arising from women at modest risk for fracture., Methods: We measured baseline BMD in a population-based random sample of 616 postmenopausal women aged 60-94 years and followed these individuals for a median of 5.6 years (IQR 3.9-6.5) to determine the incidence of fractures according to age, BMD and the presence of a prior fracture., Results: Based on WHO criteria, 37.6% of the women had normal total hip BMD, 48.0% had osteopenia and 14.5% had osteoporosis. The incidence of fracture during follow-up was highest in women with osteoporosis, but only 26.9% of all fractures arose from this group; 73.1% occurred in women without osteoporosis (56.5% in women with osteopenia, 16.6% in women with normal BMD). Decreasing BMD, increasing age and prior fracture contributed independently to increased fracture risk; in a multivariate model, the relative risk for fracture increased 65% for each SD decrease in BMD (RR=1.65, 95%CI 1.32-2.05), increased 3% for every year of age (RR=1.03, 95%CI 1.01-1.06) and doubled with prevalent fracture (RR=2.01, 95% CI 1.40-2.88). A prevalent fracture increased the risk for fractures such that women with osteopenia and prevalent fracture had the same, if not greater, risk as women with osteoporosis alone., Conclusions: Reducing the population burden of fractures requires attention to women with osteopenia, as well as osteoporosis, because over half of the fragility fractures in the population arise in these individuals, and women with osteopenia plus a prevalent fracture have the same fracture risk as women with osteoporosis.

Introduction: This is a summary of several aspects of the epidemiology, pathogenesis and treatment arising directly and indirectly from the proceedings of the Third International Osteoporosis in Men meeting held in Genoa in May 2005. Advances in the study of bone fragility in men have taken place, but many challenges remain., Observations: Although the epidemiology of hip fractures is well documented, the epidemiology of other non-vertebral fractures is less well defined even though these fractures contribute substantially to the global burden of fractures in men. The epidemiology of vertebral fragility fractures is derived mostly from cross sectional data. The comparable prevalence of vertebral fractures in men and women is likely to be misleading because of traumatic vertebral fractures that arise in young men. Prospective studies are needed to define the proportion of these fractures that are traumatic. After the age of 50 years, the incidence of vertebral fractures in men is about one third to one half of that in women. As in women, most vertebral and non-vertebral fragility fractures occur in persons without osteoporosis. Identifying these individuals is an unmet challenge. The absolute risk for fractures appears no different by sex in men and women of the same age and bone mineral density (BMD) so that the diagnostic threshold for osteoporosis in women can be used in men. Fracture risk varies around the world and is unlikely to be explained solely by variations in BMD, though there are few data comparing men and women of different races. Both the notion that men lose less bone than women from the endosteal envelope and that they gain more on the periosteal envelope during advancing age needs reassessment as recent evidence challenges these observations. Sex differences in the net gain and loss from these surfaces are likely to be site specific, and research is needed to specify this heterogeneity and the reasons for it. The independent and co-dependent effects of sex hormones and the growth hormone/insulin like growth factor 1 axis on periosteal and endosteal modeling and remodeling during growth as well as ageing are poorly defined. The anti-fracture efficacy and safety of androgens and other agents remain incompletely investigated in men., Conclusion: A great deal of research is needed to advance our understanding of bone fragility in men.

Structural failure becomes increasingly likely as the load on bone approximates or exceeds the bone's ability to withstand it. The vertebral fracture risk index (FRI) expresses the risk for structural failure as a ratio of compressive stress (load per unit area) to estimated failure stress, and so should be a more sensitive and specific predictor of vertebral fracture than spine areal BMD (aBMD) or volumetric BMD (vBMD), surrogates of bone strength alone. To address this issue, we analyzed the results of a case-control study of 89 postmenopausal women with vertebral fractures and 306 controls in Melbourne, Australia, and a 10-year community-based prospective study in which 30 postmenopausal women who had incident vertebral fractures were compared with 150 controls in Lyon, France. The FRI and vBMD of the third lumbar vertebral body and spine aBMD were derived using dual X-ray absorptiometry. In the cross-sectional analysis, each SD increase in FRI was associated with 2.1-fold (95% confidence interval [CI], 1.55-2.73) increased vertebral fracture risk, while each SD decrease in aBMD or vBMD was associated with 4.0-fold (95% CI, 2.69-6.18 and 2.65-6.94, respectively) increase in risk. Using receiver operating characteristic (ROC) analysis, the FRI was less sensitive and specific than aBMD in discriminating cases and controls (area under ROC, 0.76 vs 0.84, p<0.01). The area under ROC curve did not differ between FRI and vBMD (0.76 vs 0.79, NS). In the prospective data set, the FRI was not predictive [hazard ratio, HR, 1.20 (95% CI, 0.9-1.7)] and was in contrast to aBMD [HR, 2.4 (95% CI, 1.5-3.8)] and vBMD [HR, 2.1 (95% CI, 1.39-3.17)]. There was also lower sensitivity using a cutoff value of FRI>or=1 compared with aBMD T-score of -2.5 SD in both studies. There was poor agreement (kappa=0.13-0.18) between FRI and aBMD T -scores in detecting fractures; each method only identified around 50% of fractured cases. Within the constraints of the sample size, we concluded that applying a biomechanical index such as FRI at the spine is no better in discriminating fracture cases and controls than conventional aBMD or vBMD. The FRI may not predict incident vertebral fractures.

The aim of the study was to identify associations between fractures in childhood and family, anthropometric and lifestyle factors. Among 1,246 subjects aged 16.3-20.6 years (539 boys, 707 girls), based on a questionnaire, 869 were fracture-free while 377 (30.26%) had fractures. Of those reporting fractures, 146 reported multiple fractures (12% of studied population, 39% of all fractures). More boys had fractures than girls (35.6% vs 24.9%, p < 0.001). Fracture sites included: forearm (37%), fingers (23%) wrist (16%), ankle (14%), humerus (10%), tibia (8%) clavicle (7%) and femoral shaft / neck (3%). Among adolescents with multiple fractures, 52% also reported fractures in at least one family member, compared with 29% of those without a fracture history. Fractures in siblings and mothers (but not fathers) accounted for 44% of the liability in adolescents' fractures. Subjects with multiple fractures reported more time at the computer than those without fractures and reported more time participating in team sports, and 18.6% avoided milk, whereas 12.4% of those without fractures reported milk-free diets. Using a logistic regression model, none of the lifestyle factors, except for computer use, were independently associated with fractures. Fractures, particularly multiple fractures, are common in childhood and adolescence. Familial clustering of fractures suggests shared genetic and environmental factors are responsible.

Exercise and improved nutrition offer safe, low-cost and widely applicable approaches to potentially reduce the burden of fractures. We conducted a cross-sectional study of 30 monozygotic and 26 dizygotic male twin pairs, aged 7-20 years to test the following hypotheses: (1) Associations between bone mass and dimensions and exercise are greater than between bone mass and dimensions and protein or calcium intakes; (2) exercise or nutrient intake are associated with appendicular bone mass before puberty and axial bone mass during and after puberty. Total body and posteroanterior (PA) lumbar spine bone mineral content (BMC) and mid-femoral shaft dimensions were measured using dual energy X-ray absorptometry (DEXA). Relationships between within-pair differences in nutrient intake (determined by weighed-food diaries) or exercise duration (determined by questionnaire) and within-pair differences in BMC and bone dimensions were tested using linear regression analysis. In multivariate analyses, within-pair differences in exercise duration were associated with within-pair differences in total body, leg and spine BMC, and cortical thickness. Every-hour-per-week difference in exercise was associated with a 31-g (1.2%) difference in total body BMC, a 10-g (1.4%) difference in leg BMC, a 0.5-g difference in spine BMC and a 0.1-mm difference in cortical thickness ( p <0.01- p <0.1). A 1-g difference in protein intake was associated with a 0.8-g (0.4%) difference in arm BMC ( p <0.05). These relationships were present in peri-pubertal and post-pubertal pairs but not in pre-pubertal pairs. Exercise during growth appears to have greater skeletal benefits than variations in protein or calcium intakes, with the site-specific effects evident in more mature twins.

In this population-based study, we evaluated the association between exposure to hormone therapy (HT), bone mineral density (BMD) and the prevalence of non-vertebral fractures. The study was set in a region located in southeastern Australia where complete fracture ascertainment was determined from radiological reports. Current HT use for at least 6 months was ascertained in women with non-vertebral fractures [median age 70.9 years; inter-quartile range (IQR) 66.5-75.9 years] and randomly selected controls (median age 70.8 years; IQR 65.2-75.0 years). Current HT use was documented in 20 of 262 cases and 49 of 364 controls. The odds ratio (OR) for non-vertebral fracture associated with HT use was 0.53 (95% CI 0.31-0.92). HT use was associated with 2.6-7.5% higher BMD at axial and appendicular sites. HT use is associated with a halving of risk for non-vertebral fractures and higher BMD.

To gain insight into the growth- and age-related origins of bone fragility at the proximal femur, we analyzed structural and biomechanical data of the femoral neck from a study of postmenopausal women with hip fractures and their 47 premenopausal daughters. Results were expressed as standard deviations (SD) or Z-scores (mean +/- SEM) adjusted for age and weight, derived using a normal reference population of 262 premenopausal women and 370 postmenopausal women. Women with hip fractures had increased femoral neck (FN) periosteal and endocortical diameters (1.01 +/- 0.26 SD and 1.18 +/- 0.25 SD, respectively). Cortical thickness was reduced by 0.96 +/- 0.1 SD and volumetric bone mineral density (vBMD) was reduced by 1.2 +/- 0.1 SD). The section modulus was normal while the buckling ratio was increased by 1.59 +/- 0.17 SD). Their daughters had increased FN diameter by about one half that of their mothers (0.48 +/- 0.16 SD), while endocortical diameter was increased by only one third (0.44 +/- 0.13 SD). Cortical thickness and vBMD were not reduced, the section modulus was increased (0.48 +/- 0.13 SD) while the buckling ratio was normal. We infer that the larger femoral neck size in women with hip fractures is growth-related; the wider endocortical cavity and thinner cortex is the result of excessive age-related endocortical bone resorption producing a thin cortex in a larger bone predisposing to structural failure by local buckling. The structural basis of bone fragility has some features originating during growth and others during aging.

We studied 112 healthy men and 261 healthy women aged 18-92 years, and 34 men and 73 postmenopausal women with vertebral fractures aged 45-90 years to determine (i) whether patients with vertebral fractures have shorter stature before fracture, and (ii) whether the difference between arm span and standing or sitting height can be used to identify patients with fractures. Arm span was measured by using a calibrated extended ruler. Standing height, sitting height and leg length were measured by using a Holtain stadiometer. The results were expressed in absolute term and standard deviation (SD) or Z-scores (mean+/-SEM). Advancing age was associated with decreased sitting height (r=-0.37 to -0.41, both P<0.01) and a trend towards decreased arm span (r=-0.12 to -0.17, P=0.06 and 0.07) in healthy men and women; leg length was independent of age in both sexes (r=-0.09 to -0.12, NS). In patients with vertebral fractures, sitting height was reduced in women (Z=-0.83+/-0.14 SD, P<0.01) and men (Z=-1.37+/-0.21 SD, P<0.01) but only the women had reduced leg length (Z=-0.46+/-0.15 SD, P<0.01) and arm span (Z=-0.76+/-0.15 SD, P<0.01). Univariate and multivariate analyses suggest that the predictive ability of the difference between arm span and standing or sitting height to identify patients with vertebral fractures is limited. We concluded that women, not men, with vertebral fractures may come from a population with short stature. The difference between arm span and standing or sitting height cannot be used to predict vertebral fracture risk.

Osteoporosis and fragility fractures are believed to be uncommon in Africa. To reevaluate this notion, we documented all patients aged 35 years and older admitted to the two main urban hospitals in Cameroon following a diagnosis of fracture during 2 years. Among 513 patients sustaining fractures (192 women, 321 men), 13.5% of all fractures in women occurred at the hip (n=26), 4.7% at the forearm (n=9), and 81.8% (n=157) at other sites (mainly tibia and femoral shaft). In men, the corresponding figures were 9% (n=29), 1.9% (n=6), and 89.1% (n=286). Of the hip and wrist fractures occurring in women, 80.0% were low energy trauma fractures due to falls, 8.6% were high-energy trauma fractures (road accidents), and 11.4% were undefined. In men, the corresponding figures were 42.9%, 34.3%, and 22.9%. Using the 1997 estimates of the population, the annual incidence rates of low-energy trauma fractures (per 100,000 persons over 35 years and above) were 4.1 in women, 2.2 in men for hip fractures, 1.2 in women, and 0.2 in men for wrist fractures. The pattern of most of the hip and wrist fractures in women is consistent with underlying bone fragility. The low incidence of fragility fractures is confirmed and is likely to be, in part, the result of reduced longevity as only 1.1% of women and 0.7% of men survive beyond 65 years of age.

The net amount of bone lost during aging is determined by the difference between the amount of bone removed from the endocortical, trabecular and intracortical components of its endosteal (inner) envelope and formed beneath its periosteal (outer) envelope. Endosteal bone loss is determined by the remodeling rate (number of basic multicellular units, BMUs) and the negative balance (the difference between the volumes of bone resorbed and formed in each BMU). Bone loss already occurs in young adult women and men and is probably due to a decline in the volume of bone formed in each BMU. The rate of loss is slow because the remodeling rate is low in young adulthood. Bone loss accelerates in women at menopause because remodeling intensity increases and BMU balance becomes more negative as estrogen deficiency reduces osteoblast lifespan and increases osteoclast lifespan. The high remodeling rate also reduces the mineral content of bone tissue. The negative BMU balance results in trabecular thinning, disappearance and loss of connectivity, cortical thinning and increased intracortical porosity. These changes compromise the material and structural properties of bone while concurrent age-related subperiosteal bone formation increases the cross-sectional area (CSA) of bone partly offsetting endosteal bone loss and the loss of structural and material strength. Thus, treatments aimed at reducing the progression of bone fragility, and reversing it, should reduce activation frequency and so reduce the number of remodeling sites, reduce osteoclastic resorption in the BMU, and so reduce the volume of bone resorbed on each of the three components of the endosteal surface thereby reducing the progression of trabecular thinning, loss of connectivity, cortical thinning and porosity. If treatment also increases periosteal bone formation, the CSA of the whole bone and its cortical area will increase. If treatment also increases endosteal bone formation in the BMU, bone balance will be less negative, especially if resorption depth is reduced. This may produce thickening of trabeculae provided activation frequency is not too low. If treatment can increase de novo bone formation at quiescent endosteal surfaces, this will increase cortical and trabecular thickness, and reduce intracortical porosity. In this way, drugs directed at both the resorptive and formative aspects of remodeling, and bone modeling may (i) increase compressive and bending strength of cortical bone by increasing the diameter of the whole bone, its CSA and the distance the cortical mass is placed from the neutral long bone axis; (ii) maintain or increase peak compressive stress and peak strain in trabecular bone, preventing microcracks and buckling; and (iii) increase the material density of bone tissue, an effect that probably should not be permitted to reach a level which reduces resistance to microdamage accumulation and progression (toughness).

The reduced bone mineral density (BMD) found in patients with fractures may, in part, follow rather than precede the fracture. We studied the magnitude and reversibility of bone loss in the 15 months following osteotomy in 21 men and 5 women with localized medial arthritis of the knee. BMD (mean +/- SD), measured using dual-energy X-ray absorptiometry, decreased by a maximum of 35 +/- 21% in the mid-diaphysis of the affected tibia at 9 months after surgery (p < 0.001). At 15 months, reversal of bone loss in non-fractured bones was incomplete; the remaining deficit was 20 +/- 27% relative to baseline (p < 0.001). Maximum bone loss occurred at 9 months at the total body (5 +/- 2%), spine (15 +/- 17%) and at Ward's triangle of the proximal femur of the unoperated limb (10 +/- 17%) (all p < 0.01). In summary, post-traumatic bone loss is region-specific with incomplete reversibility, at least after about 15 months. Deficits in BMD in cross-sectional studies of patients with fractures, held to be responsible for the bone fragility, may, in part, follow rather than precede the fracture.

Biochemical measurements of bone turnover are helpful in the study of the pathophysiology of skeletal metabolism and growth. However, interpretation of their results is difficult because they depend on age, pubertal stage, growth velocity, mineral accrual, hormonal regulation, nutritional status, circadian variation, day-to-day variation, method of expression of results of urinary markers, specificity for bone tissue, sensitivity and specificity of assays. Three markers of bone formation have been described including their bone specificity and age-related changes: osteocalcin, alkaline phosphatase and its skeletal isoenzyme, procollagen I extension peptides. Bone resorption markers (hydroxyproline; deoxypyridinoline; pyridinoline; peptides containing these crosslinks such as N-telopeptide to helix in urine (NTX), C-telopeptide-1 to helix in serum (ICTP) and C-telopeptide-2 in urine and serum (CTX); tartrate-resistant acid phosphatase; hydroxylysine and its glycosides) are described with special attention to methodologic issues, mainly ways of expression of their results. Changes of bone turnover during growth are described during four periods: infancy, prepubertal period, puberty and the postpubertal period. Pubertal changes of bone markers are described with special attention to gender differences and hormonal mechanisms of the growth spurt which determine differences related to the pubertal stage. Disturbances of bone turnover in four conditions are described to illustrate the impact of such diseases on growth and formation of peak bone mass: prematurity, malnutrition, growth hormone deficiency and corticosteroid-treated bronchial asthma. Available data suggest biochemical markers of bone remodeling may be useful in the clinical investigation of bone turnover in children in health and disease. However, their use in everyday clinical practice is not advised at present.

Alendronate has been reported to increase bone mineral density (BMD) and reduce fracture risk in women with osteoporosis. As there are no proven safe and effective treatments available for men with osteoporosis, we compared the effects of alendronate (10 mg/day) on BMD, measured using dual-energy X-ray absorptiometry, in a 12-month prospective, controlled, open label study involving (i) men with primary (n = 23) or secondary osteoporosis (n = 18), (ii) postmenopausal women with primary (n = 18) or secondary (n = 21) osteoporosis, and (iii) 29 male and 14 female untreated controls matched by age, height and weight. The patients had one or more vertebral fractures and ranged in age from 34.6 to 85.1 years. BMD was detectably increased relative to baseline by 6 months, and increased by comparable amounts in males and females with primary or secondary osteoporosis. At 12 months, lumbar spine BMD was 5.4% +/- 1.1% to 7.0% +/- 2.2% higher in the treated groups compared with baseline and controls (p < 0.05 to 0.0001). Trochanteric BMD increased by 2.6% +/- 1.5% and 3.7% +/- 1.7% in treated men with primary and secondary osteoporosis, respectively (p = 0.06 to 0.08), and by 3.9% +/- 1.3% in treated women with primary osteoporosis (p < 0.01) after 12 months. No significant changes were detected at the femoral neck or Ward's triangle. BMD remained unchanged in controls. We infer that alendronate has comparable incremental effects on BMD in men and women with primary and secondary osteoporosis within 12 months of treatment. The changes are in the order of 0.5 SD--effects associated with a clinically worthwhile reduction in fracture risk. The data provide room for optimism regarding the role of alendronate in the treatment of osteoporosis in men. Randomized, double-masked and placebo-controlled trials are needed to confirm these preliminary findings and demonstrate antifracture efficacy using vertebral and nonvertebral fracture rates as the primary endpoint.

Hip axis length (HAL) has been reported as an independent risk factor for hip fracture. Later puberty may increase bone size because of delayed epiphyseal fusion. We sought to identify associations between bone size at the proximal femur with age at menarche and other indices of growth such as stature. Femoral neck dimensions were measured from dual-energy X-ray absorptiometry scans of the proximal femur in a random sample of 203 premenopausal Caucasian women (age 20-30 years). There were no associations between age at menarche and HAL, femoral axis length (FAL) or femoral neck width (FNW). Age at menarche was associated with height (r = 0.2, p = 0.02). Variations in HAL, FAL and FNW do not appear to be related to age at menarche.