Osteoporos Int Research Articles

Postmenopausal bone loss in human skeletal remains of a historical population of southeastern France

Dear Editor, The existence of osteoporosis in past populations is controversial. In archeological samples, age-dependent bone loss is considered as less frequent [1], similar [2–4] than nowadays or not determinable [5]. We have hypothesized that age-related bone loss was present in the past populations and can be evaluated by comparing the bone density of young and elderly women. We studied 90 skeletons from the cemetery of the crypt of the Notre-Dame-du-Bourg cathedral in Digne, Alpes-deHautes-Provence, France, burial place of the inhabitants of the city from 11th to 17th century without known social discrimination. The sex was determined by the morphology of the coxal bone. We selected two clearly separated age groups samples, i.e., under 30 years (juvenile sacral joint or incomplete fusion of the iliac crests, and/or ongoing eruption or no wear of the third molars), over 50 years (compatible sacro-iliac joint features). We studied the femurs of 17 young and 40 elderly women and 9 young and 24 elderly men selected within two periods of the cemetery (i.e., 11th–13th: 7 young women, 10 elderly women, 4 young men, 10 elderly men; 16th–17th: 10 young women, 30 elderly women; 5 young men, 14 elderly men). All femurs were devoid of traumatic, pathologic lesions and postmortem deterioration. Bone mineral density was measured at the femoral neck (BMD neck) and at the Ward’s triangle region (BMD Ward) using a LUNAR DPXL dual energy X-ray absorptiometer. The femurs were supported at the head and lesser trochanter and scanned immersed in a water tank at a depth of 15 cm. Statistical analysis was performed using the MannWhitney test (conventional level : 0.05). Duplicate measurements on 22 femurs indicated good reproducibility (coefficient of variation : Neck : 4.5% ; Ward : 7.6%). For 30 pairs of femurs BMD values were not different between the two sides (Neck: p=0.24, Ward: p= 0.16). The BMD neck and Ward of the elderly women were statistically lower than those of the young women (Table 1). The BMD of the elderly men was only lower for the neck. Most of elderly women had BMD lower than the mean less two standard deviations of the young women (neck: 27/ 40; Ward: 28/40). Corresponding comparisons for men showed relatively lower densities for only 2 of 24 for the two sites. These results support our hypothesis of a significant bone loss among the elderly women in this historical sample and confirm recent studies [2–4]. Opposite results are related with smaller samples and/or methodological differences. The soil contact was not a confounding factor considering the similar repartition of the femur samples through time and that this study was only focused on the gap between young and elderly. The sample size reduces the likelihood of other demineralizing diseases. The gap between young and elderly females appears greater than nowadays, but the osteological methods used Osteoporos Int DOI 10.1007/s00198-007-0444-7

Individualization of osteoporosis risk

Anti-fracture therapy is often pursued in individuals with osteoporosis or low bone mineral density with or without a prior fracture [1–3], because they are at high risk of subsequent fracture [4, 5]. In recent years, there has been a proliferation of clinical prediction rules, including clinical risk indices and scores, for identifying individuals with osteoporosis. The main problem with these clinical prediction rules is that they categorize individuals into low-risk versus high-risk groups based on some arbitrary threshold. As a result, when this risk stratification-based approach is applied to an individual, its prognostic performance is often poor. Among the clinical indices for predicting osteoporosis, the Osteoporosis Self-Assessment Tool (OST) [6] is perhaps the simplest score and has perhaps been the most widely studied. However, the clinical usefulness of this score in different populations has not been systematically studied. In this issue, Rud and colleagues [7] systematically summarize some key prognostic properties of the OST score across different Asian and Caucasian populations. They especially focus on the prognostic value of OST in ruling out osteoporosis (i.e., LR−). Their meta-analysis showed that the overall LR− was 0.19 (95% confidence interval: 0.17 and 0.21) with considerable heterogeneity between populations. Although Rud and colleagues do not report other prognostic measures of the OST score in their paper, it is possible to estimate the LR+, sensitivity, specificity, and summary receiver operating characteristic curve (sROC) from the data (Table 1). These results suggest that in both Asian and Caucasian populations, the OST score has good sensitivity, but poor specificity, and moderate discriminatory value (i.e., with sROC being between 0.74 and 0.79). The odds for OST positivity among women with osteoporosis is 11 times (in Asians) and 7.8 times (in Caucasians) higher than the odds for positivity among women without osteoporosis. This diagnostic odds ratio is much lower than the criterion required for an “adequate test”. However, these results are broadly consistent with prognostic values of the simple calculated osteoporosis risk estimation (SCORE), osteoporosis risk assessment instrument (ORAI) and National Osteoporosis Foundation guidelines, which were also found to have poor specificity and high sensitivity [8]. When the prevalence of osteoporosis is 17% (which is observed in Caucasian populations [7]) and given the observed LR− and LR+ in Table 1, it can be estimated that if an individual is classified as “low risk” by OST, the probability that the individual has no osteoporosis is 0.96; and if the individual is classified as “high risk”, the probability that the individual has osteoporosis is only ~0.25. In other words, the OST score is useful in ruling out the possibility of osteoporosis, but it performs badly in ruling in the possibility of osteoporosis. The best positive and negative predictive values are achieved when the sensitivity is around 70% and specificity is approximately 80% (Fig. 1). However, in all studies reviewed, the OST score has a sensitivity of >90% and specificity of <57%. Several factors contribute to the relatively poor performance of OST. First, the prevalence of osteoporosis in the populations under review, and the relationships between age, weight and BMD is not constant across the population. For example, the prevalence of osteoporosis varied between 7 to 21%, with and the LR− being between 0.02 and 0.49 among the Asian populations under review. Indeed, a Osteoporos Int (2007) 18:1153–1156 DOI 10.1007/s00198-007-0415-z

Hypovitaminosis D and secondary hyperparathyroidism in the elderly: risk factors for hip fracture or markers of frailty?

Dear Editor, In a recent issue of Osteoporosis International Sakuma et al. demonstrated a higher prevalence of hypovitaminosis D and secondary hyperparathyroidism (sHPTH) in elderly patients with hip fracture than in non-osteoporotic controls [1]. One of the conclusions of the authors was that serum 25hydroxyvitamin D (25-OHD) may be a useful index to identify elderly at high risk of hip fracture. We found these results interesting and, although in agreement to some degree, we would raise some issues in order to contribute to the topic. It is well established that, in the general population, the frequency of vitamin D deficiency and sHPTH increase with the age and are higher in subjects with functional disability [2]. In the study by Sakuma et al., patients with femoral fracture were older compared to controls, and their serum level of 25-OHD was related to the degree of functional dependence. However, no comparison of baseline functional status between the two groups was reported. Moreover, hip fractured subjects presented serum albumin levels significantly lower than controls, with the difference being significant even after controlling for age. In elderly people, serum albumin is considered to be a marker of frailty rather than a simple nutritional index – a term commonly used to describe elderly individuals particularly vulnerable to falls, disability and premature death [3]. A spontaneous consideration arising from these observations is that patients in the hip fracture group not only were more likely to have sHPTH and hypovitaminosis D, but, more importantly, presented a higher degree of frailty compared to controls. Consistent with these observations, we have recently demonstrated, in a cohort of older adults with and without hip fracture, a strong correlation between the ability to perform basic activities of daily living (BADLs) and sHPTH due to hypovitaminosis D [4]. Moreover, in our report, after normalizing for age and baseline functional status, there was no significant difference in terms of prevalence of sHPTH between hip fractured subjects and matched controls. It, therefore, seems that 25-OHD deficiency and sHPTH, along with serum albumin, more than simple risk factors for hip fracture, may be considered to be a useful index to identify vulnerable and frail older adults. In support to these hypotheses, it must be noted that some studies have demonstrated a strong correlation between sHPTH, due to hypovitaminosis D, and a number of adverse outcomes in elderly subjects [5, 6]. Di Monaco et al. found that PTH and 25-OHD, acting through independent mechanisms, were significantly associated with the functional recovery after hip fracture [5]. Furthermore, Sambrook and colleagues found that PTH was significantly associated with increased mortality in older adults residing in hostels and nursing homes, independently of renal function, bone mass and vitamin D status [6]. Osteoporos Int (2007) 18:1561–1562 DOI 10.1007/s00198-007-0395-z

A novel mutation in the LRP5 gene is associated with osteoporosis-pseudoglioma syndrome

Dear Editor, Osteoporosis-pseudoglioma syndrome (OPPG) is an autosomal recessive disorder characterized by low bone mass and ocular globe alterations, with frequent fractures as a consequence of high skeletal fragility and severe visual deficiency [1]. Recently, Gong et al. identified mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) that cause OPPG [2]. The LRP5 gene is located on the long arm of chromosome 11 at 11q13.4, has 23 exons, and encodes a transmembrane protein with 1,615 amino acids. This protein is a member of the low-density lipoprotein receptor (LDLR) family, the members of which have very well conserved characteristics. We had the opportunity to follow-up two brothers with clinical characteristics of OPPG, and we decided to investigate the LRP5 gene to identify any mutation that could explain the clinical features of low bone mass, fractures, and blindness. The older brother came to the hospital when he was 12 years old, (53 kg; 157 cm). At that time, lumbar bone mineral density (BMD, Hologic 4,500 A) was 0.512 g/cm (Z score −3.99). He was born blind, had a normal development until the age of 7 years, when he had lumbar pain due to the fracture of a vertebral body. At the age of 11, pain in the left leg led to the diagnosis of a tibial fracture. One month later, the same occurred in the right tibia and 2 months after that, a fracture in the right femur was detected, and he was referred to our hospital. The younger brother was 4 years old at that time and was born blind. At 2.5 years, he had a fracture of the right femur after a small fall. He was eutrophic (13 kg and 97 cm), with a lumbar BMD of 0.277 g/cm2 (Z score −5.4). Both of them had normal biochemical and hormonal parameters. Their parents were consanguineous, had normal BMD and no history of fractures or blindness, and there were no similar cases in the family. The 23 exons were analyzed and we identified an LPR5 missense mutation in the third codon of exon 8, in which an asparagine is replaced by isoleucine (N531I) in two siblings with OPPG and their consanguineous parents. The patients were found to be homozygous for this mutation, while their parents are heterozygous. This amino acid is located at the second propeller domain (YWTD repeat) in the extracellular domain of the receptor. Fifty normal participants underwent analysis of this exon, and the mutation was not present in any of them, but a polymorphism C→T (rs545382 NCBI, F549F) was found at a frequency of 1:5. According to Sidow’s program [3] of multivariate analysis of protein polymorphism (MAPP), we observed that the N531I mutant scored higher (yielding a bad amino acid substitution) and this mutation is located in the group of deleterious variants because of its high degree of evolutionary conservation. Based on these facts, we believe that this mutation is responsible for the clinical features presented in our patients and thereby define a novel mutation that causes OPPG in humans. Osteoporos Int DOI 10.1007/s00198-007-0360-x

Estimates of fracture probability in Denmark

Dear Editors, The predictive value of DXA for fracture risk assessment has been established in many studies. The meta-analysis of Marshall et al. [1] found that the risk of any osteoporotic fracture increased 1.6-fold for each standard deviation decrease in bone mineral density. More recently it has become evident that there are important interactions that modulate the performance characteristics of BMD. For example, age provides an element of risk not captured by BMD. Thus, the 10-year probability of hip fracture in women aged 80 years with a T-score of −2.5 SD at the femoral neck is fivefold higher than that found in a woman at the age of 50 years with an identical T-score [2]. There is also a complex interaction of age with BMD. Whereas the average gradient of risk for hip fracture in men and women is approximately 2.6 per SD decrease in BMD at the femoral neck [1], it is significantly higher at the age of 50 years (3.68) than at the age of 85 years (1.93) [3]. More recently it has been possible to combine the primary data from a large number of population-based cohorts to elucidate the independent contribution of other clinical risk factors for fracture over and above that provided by age and BMD. Candidate risk factors include low body mass index, the long-term use of glucocorticoids, a prior fragility fracture, a parental history of hip fracture, secondary causes of osteoporosis, cigarette use and excess alcohol consumption [4]. Because of the multiplicity of independent risk factors and their complex interactions, there is a growing view that for clinical purposes, fracture risk should be expressed as fracture probability. The approach takes into account both the risk of fracture and of death [5]. In a recent paper Abrahamsen et al. [6] present their findings on the 10-year absolute risk of osteoporotic fractures according to the T-score for BMD at the total hip. They found that absolute risk in young postmenopausal women in Denmark was higher for any BMD value than that presented by us for Sweden in 2001 [2]. We would agree with this finding. The authors also suggest that the gradient of risk between BMD and fracture risk (i.e., the increase in risk for each standard deviation decrease in BMD) differs from our findings as illustrated in their figure (Fig. 2 of their paper). On this basis, the authors state that “the Kanis algorithm is of limited use at the time of the menopause”, and “is certainly true in healthy North European women not only because the gradient of risk differs from our work but also because the absolute risk differs”. The ‘Kanis algorithm’ is a term commonly associated with the models for fracture risk assessment that our WHO Collaborating Centre is developing. In this context, the statements of Abrahamsen are misleading and should not go unchallenged. Osteoporos Int (2007) 18:1141–1143 DOI 10.1007/s00198-007-0346-8

Unmet needs in fracture prevention: new European guidelines for the investigation and registration of therapeutic agents

Recognition of the problem of age-related bone fragility emerged in the middle of the last century when Fuller Albright drew attention to the common occurrence of vertebral fractures in postmenopausal women [1]. With increasing numbers of individuals living into old age, hip fractures gained recognition because of the high incidence, morbidity, mortality and cost imposed by this type of fracture [2]. More recently, several insights have emerged that require attention if the burden of fractures is to be minimized. First, although vertebral and hip fractures are important, from a global perspective, 80–90% of all fragility fractures and the disutility they cause are peripheral in origin (non-hip, nonvertebral) [3, 4]. Second, over 50% of all fragility fractures arise from the larger segment of the population with osteopenia, not osteoporosis [5, 6]. These are fragility fractures, but the basis for the bone fragility is only beginning to be defined [7]. Third, with the changing demographics of the population, over 80 year olds comprise ∼10% of the population but contribute 20–25% of all fragility fractures because this segment of the population have the highest prevalence of risk factors (osteoporosis, prevalent fractures, falls) and the highest morbidity and mortality [8]. Fourth, fractures in men are common [9]. Fifth, two major impediments to fracture prevention are failure of uptake of treatments and failure of adherence to treatment in 50% within 12 months of initiating treatment [10]. These issues are compounded by corresponding deficiencies in treatment. Vertebral fracture risk reduction, although credibly reported with several agents, is only 30–50% [11]. Anti-hip fracture efficacy is also only 30– 50% and has only been reported with alendronate, risedronate [11], and zoledronate [12]. Anti-hip fracture efficacy has also been reported in a post hoc analysis with strontium ranelate [13]. Hip fracture risk reduction has been studied as a primary endpoint in only one pivotal trial and several smaller studies with risedronate [11, 14–16]. For peripheral (non-vertebral non-hip) fractures, fracture risk reduction is modest, 16 to 20%, and has been demonstrated with risedronate, PTH 1–34 and strontium ranelate [11], but planned as a primary endpoint only with strontium ranelate [13]. Peripheral fracture risk reduction has also been reported with alendronate in the FOSIT study and after pooling of patients in the fracture intervention trial (FIT 1) with those patients with osteoporosis in FIT 2 [11, 17]. Issues concerning the design and execution of trials of calcitonin, calcitriol and other vitamin metabolites make inferences concerning anti-fracture efficacy difficult. Recent studies of calcium supplementation had methodological problems, particularly compliance [18–20]. Although lower fracture rates in compliers were reported in each trial is encouraging, whether this was due to the calcium supplement is uncertain. Random allocation assures that known and unknown confounders that independently influence fracture rates are equally prevalent in placebo and calcium arms. With adherence of ∼50%, this assurance is lost. In women with osteopenia alone, only raloxifene and strontium ranelate have been reported to reduce vertebral fracture risk [21, 22]. Alendronate has also been reported to reduce vertebral fracture risk in women with osteopenia and Osteoporos Int (2007) 18:569–573 DOI 10.1007/s00198-007-0350-z

Elevated plasma concentration of homocysteine, low level of vitamin B6, pyridoxal, and vitamin D insufficiency in patients with hip fracture: a possible explanation for detrimental cross-link pattern in bone collagen

Impaired bone quality has been proposed as a cause of increased bone fragility in osteoporosis. Collagen crosslinking is a candidate for determining the material properties of bone. Collagen cross-links are of two types; lysyl oxidase (LOX) and lysyl hydroxylase (PLOD1; LH1, PLOD2; LH2b) controlled cross-links, and advanced glycation end products, pentosidine. Homocysteine and vitamin B(6) (pyridoxal) are also regulatory factors of collagen crosslinking. Recently, we reported that in the femoral neck fracture cases, not only reduced enzymatic cross-links in old osteon and increased pentosidine in both young and old osteons from cortical and cancellous bone, but also higher plasma homocysteine and lower pyridoxal levels were evident compared with the controls (Osteoporos Int 2006. Calcif Tissue Int, 2006). In this review, we describe that mildly hyperhomocysteinemia, and vitamin B(6) or vitamin D insufficiency are crucial determinants of detrimental crosslinking of bone collagen in patients with hip fracture.

Calcium-PTH-vitamin D axis in older patients with hip fracture

We read with interest the article by Sakuma and colleagues [1] dealing with the controversial issue of vitamin D-PTH status in hip fracture (HF) patients. With an ageing population and exponentially increasing numbers of HFs worldwide, it is important to clarify the contribution of abnormalities in calcium-PTH-vitamin D relationships to HFs. Adequate vitamin D-PTH status is paramount in calcium homeostasis and for bone health. However, recent large randomised controlled trials [2–4] as well as systemic reviews [5–7] contrary to a previous meta-analysis [8] did not find that supplementation with vitamin D and calcium reduces HFs, except in frail people confined to institutions [7]. Sakuma et al. [1] demonstrated that 62% of 50 HF patients had vitamin D insufficiency, defined as serum 25hydroxyvitamin D (25(OH)D) concentration less than 50 nmol/l, and this was associated with elevated PTH (>65 pg/ml) levels in 19.4%. We would like to add further evidence to support the harmful effects of abnormal CaPTH-vitamin D status in this population and emphasise some new dimensions to this topic. In 501 consecutive patients aged 60 years and older (mean 81.9±8.1 (SD) years, 73% females) admitted to our hospital with non-pathological minimal trauma HF we measured serum 25(OH)D, intact PTH, calcium, phosphate, magnesium, albumin, haemoglobin and creatinine; in 230 patients we also evaluated the bone turnover markers: serum osteocalcin (OC) and bone specific alkaline phosphatase (BAP) and urine deoxypyridinoline (DPD) and N-terminal cross-linking telopeptide of type I collagen (NTx). Demographic and clinical characteristics were prospectively recorded in all patients. Mean serum 25(OH)D concentration was 36.3±17.1 (SD) nmol/l. The prevalence of 25(OH)D insufficiency ( 6.5 pmol/l) indicating secondary hyperparathyroidism (SHPT), presented only in 45.7% of patients with 25(OH)D insufficiency, while in the other half of these patients the PTH level was in the normal range. A similar observation has been reported by Sahota et al. [12]. In Sakuma’s series, in about 80% of HF patients with 25(OH)D insufficiency the serum PTH level was not elevated. There was no correlation between PTH and 25 (OH)D levels in HF patients in both Sakuma’s (r=−0.17; p>0.05) and our study (r=−0.10; p=0.114) These findings demonstrate that in older HF patients, as well as in general in patients with osteoporosis [13–15], SHPT is not a universal response to hypovitaminosis D. In other words, contrary to the hypothesis that predicts increase in PTH secretion following decrease in serum 25(OH)D concentrations, the PTH level in 50% (whites) to 80% (Asians) of HF patients with vitamin D insufficiency remained in the normal range. This has been defined as “functional hypoparathyroidism” [12, 13]. These data show heterogeneity in the HF population in regard to the complex and still poorly understood vitamin D-PTH relationship. The mechanism underlying the defect in PTH response to vitamin D deficiency is unclear and may be related to an abnormality in the calcium-sensing receptor, which plays a central role in regulating PTH gene expression, PTH synthesis and secretion, and/or dysregulation in PTH gene transcription or Osteoporos Int (2007) 18:693–695 DOI 10.1007/s00198-006-0284-x

Low-carbohydrate, high-protein diets that restrict potassium-rich fruits and vegetables promote calciuria

In a recent issue of Osteoporosis International, Carter et al. reported that subjects adhering to a ketogenic, lowcarbohydrate/high-protein (LCHP) diet for weight loss did not display increased bone turnover markers after 3 months compared to control subjects consuming a typical, unrestricted diet [1]. In this trial, weight loss averaged 6.4 kg versus 1.1 kg in the dieters and controls respectively (p=0.0008), whereas the mean urinary N-telopeptide increased by 1.6 versus 1.9 nmol BCE/mmol creatinine in the dieters and controls, respectively (p=0.86). Although this trial supports the view that high-protein diets do not adversely affect bone [2, 3], the dietary level of alkalizing minerals was not considered. High-protein diets generate excessive amounts of acid due to the obligatory catabolism of sulfur amino acids, and bone may respond by releasing basic salts into the circulation [4]. Hence, if high-protein intakes are not accompanied by an adequate intake of alkalizing minerals, which have a neutralizing effect in vivo, bone health may be adversely affected [4–6]. Here we discuss unpublished data regarding acid/base metabolism from our recent trial comparing ketogenic and nonketogenic LCHP diets [7]. In this trial, 19 adults (body mass index: 34.4T1.0 kg/m) were randomly assigned to a ketogenic LCHP diet (k-LCHP; 60% of energy as fat; 5% energy as carbohydrate) or to a nonketogenic LCHP diet (n-LCHP; 30% of energy as fat; 40% of energy as carbohydrate). The n-LCHP diet was composed mainly of low-fat dairy products, fruits and vegetables, and low-fat meats, whereas the k-LCHP diet consisted primarily of high-fat meats and some vegetables. The diets were similar in protein content (~20 g/mJ), but daily intakes of potassium (1,935 versus 3,535 mg) and calcium (715 versus 1,110 mg) were markedly different for the k-LCHP versus n-LCHP diets. Blood and urine samples were collected at baseline and at week 2. Weight loss, blood ketone concentrations and anion gap values, and urinary calcium concentrations at baseline and week 2 are shown in Table 1. The blood anion gap, the interval between the sum of blood cations and blood anions, is a direct indication of the acidity of blood. For comparison, Table 1 also displays values for urine calcium calculated from predictive equations based on the dietary protein:potassium ratio [8, 9]. These data indicate that n-LCHP diets are associated with lower acid loads and lower rates of calcium excretion as compared to k-LCHP diets. Moreover, anion gap values and urinary calcium were highly correlated (r=0.542, p=0.016). Since the predicted calciuria was similar to actual values, it would appear that potassium-rich foods favorably influence acid/base metabolism and reduce calciuria. Alexy et al. [10] have presented longitudinal evidence that inadequate intakes of alkalizing minerals from fruits and vegetables may adversely impact bone health. Also, based on data from Lewis et al. [11], the calcium-rich Osteoporos Int (2006) 17:1820–1821 DOI 10.1007/s00198-006-0214-y

Poor bone quality in diabetes: detrimental collagen cross-link pattern reduces bone strength without change in bone mineral density

Although type 2 diabetes is often characterized by normal or high bone mineral density (BMD), diabetes is associated with increased risk of fracture. This paradoxical phenomenon in type 2 diabetes may be explained by poorer "bone quality" by detrimental collagen cross-links in bone. Recently, we showed that the alteration of enzymatic and nonenzymatic crosslinking in bone could be important for explaining the variation of fracture susceptibility in diabetes (Osteoporos Int, 2006. Epub ahead of print). In this review, we describe that low turnover bone, hyperglycemia, mildly hyperhomocysteinemia, and vitamin B(6) insufficiency are crucial determinants of detrimental crosslinking of bone collagen in diabetes.

A contemporary snapshot of the use of hydroxyapatite coating in orthopaedic surgery

The capacity for biological materials to combine with inorganic salts is well established. Bio-mineralisation was an evolutionary milestone, and a key contributor to the ‘cladogenesis of life’ which occurred in the early Cambrian period, 570 million years ago.[1][1] A protracted ice age in the

Buckling of adaptive elastic bone-plate: theoretical and numerical investigation

During day-to-day activities, many bones in the axial and appendicular skeleton are subjected to repetitive, cyclic loading that often results directly in an increased risk of bone fracture. In clinical orthopedics, trabecular fatigue fractures are observed as compressive stress fractures in the proximal femur, vertebrae, calcaneus and tibia, that are often preceded by buckling and bending of microstructural elements (Müller et al. in J Biomechanics 31:150 1998; Gibson in J Biomechanics 18:317-328 1985; Gibson and Ashby in Cellular solids 1997; Lotz et al. in Osteoporos Int 5:252-261 1995; Carter and Hayes in Science 194:1174-1176 1976). However, the relative importance of bone density and architecture in the etiology of these fractures are poorly understood and consequently not investigated from a biomechanical point of view. In the present contribution, an attempt is made to formulate a bone-plate buckling theory using Cowin's concepts of adaptive elasticity (Cowin and Hegedus in J Elast 6:313-325 1976; Hegedus and Cowin J Elast 6:337-352 1976). In particular, the buckling problem of a Kirchhoff-Love bone plate is investigated numerically by using the finite difference method and an iterative solving approach (Chen in Comput Methods Appl Mech Eng 167:91-99 1998; Hildebland in Introduction to numerical analysis 1974; Richtmyer and Morton in Difference methods for initial-value problems 1967).

Association of low general health status, measured prospectively by Euroqol EQ5D, with osteoporosis, independent of a history of prior fracture

There have been no studies of generic health-related quality of life (HR-QOL) measured prospectively, in patients referred for bone mass measurement. The aim of this study was to examine the relationship between HR-QOL, measured before DXA scanning was undertaken, and bone mineral density (BMD). Comparison of HR-QOL with the age- and sex-matched general population was also made. HR-QOL questionnaires were completed by patients who were being entered into a randomized, prospective, parallel group trial to assess the impact of direct access DXA scanning (DADS) versus referral to a hospital consultant, upon clinical decision making by general practitioners (GPs) (Dhillon et al., Osteoporos Int 14:326-333, 2003). HR-QOL questionnaires were completed prior to both randomization and DXA scanning. 325 patients from 18 representative general practices of a total of 77 in the city of Edinburgh. Patients had been referred by their GPs who had access to national guidelines on the identification of patients at high risk of osteoporosis. Generic HR-QOL was measured using Euroqol (EQ5D). This provides a profile of self-reported problems in five dimensions (EQ5D(profile)), health utility (EQ5D(utility)), and a visual analogue global self-rated health assessment (EQ5D(vas)). Odds ratios (ORs) for any self-reported problems on EQ5D(profile) were higher in patients with osteoporosis than those without, and compared with the general population. Age-adjusted mean (SD) EQ5D(utility )was significantly lower in patients with osteoporosis than in those without (0.65 [0.28] vs 0.76 [0.27]; p< 0.01), but the difference lessened with advancing age. Age-adjusted mean (SD) EQ5D(vas) was significantly reduced in patients with compared with no osteoporosis (68 [20] vs 76 [16]; p<0.01). There were no such differences in patients with a history of prior fracture compared with those without a history of prior fracture. Female patients with osteoporosis have reduced generic HR-QOL compared with the age-matched female general population, irrespective of a history of prior fracture. The causal relationship between osteoporosis and HR-QOL, if any, is unclear. Further studies are needed to define this relationship and to determine whether treatment of osteoporosis has a beneficial effect on HR-QOL independent of fracture risk.

Reply to letter by M. Casey and B. Walsh: Chronic renal failure in hip fracture patients

Sir, We welcome the Letter to the Editor in which M. Casey and B. Walsh recommend that renal function in elderly patients with osteoporosis and osteopenia be clarified prior to treatment with drugs impacted by renal status. The high prevalence of severe renal compromise reported by the writers in 100 patients ages 84±8.8 years undergoing operation for hip fracture is in good agreement with the high prevalence we found in women ages ‡80 years with osteoporosis in the NHANES III. Because osteoporosis treatments, such as bisphosphonates and various forms of vitamin D, as well as treatments for other conditions, may be impacted by renal dysfunction in the frail elderly, physicians can benefit these patients by an assessment of renal status in conjunction with treatment. Osteoporos Int (2004) 15: 421 DOI 10.1007/s00198-004-1586-5

Does bone density predict fractures comparably in men and women?

At the recent National Institutes of Health Consensus Development Conference on Osteoporosis Prevention, Diagnosis, and Therapy (http://odp.od.nih.gov/consensus/cons/111/111_statement.htm), there was some tension between two concepts that, upon first glance, appear contradictory: First, there is a greater relative risk of fracture per standard deviation (SD) change in bone mineral density (BMD) in women than men; and, second, the absolute risk of fracture in women and men with a given BMD level is the same. Are both of these statements true? And, if so, are these two notions really mutually exclusive? Resolution of this issue has a bearing on whether World Health Organization diagnostic criteria for osteoporosis should be the same for men as for women and whether gender should be a consideration in new approaches to bone density assessment that focus on absolute fracture risk [1–3]. In this Brief Review, we consider the available evidence bearing on these two questions and suggest that the two concepts are not contradictory. We also specify additional data that should help clarify several unresolved issues that remain. That the relative increase in fracture risk per 1 SD decline in areal BMD (g/cm) is greater in women than men has been suggested by a number of studies where the two sexes were assessed comparably [4–7]. For example, in a population-based case–control study in Rochester, MN, the age-adjusted relative risk of an osteoporotic fracture (hip, spine or distal forearm due to minimal or moderate trauma 535 years of age) was 2.4 per 1 SD decrease in femoral neck BMD in women but only 1.1 in men [7]. Other investigators have found more comparable sex-specific relative risks for osteoporotic fractures in general [8] and for spine [9–11] and hip fractures [12,13] in particular. In the Rotterdam study, for example, the age-adjusted relative risk of hip fracture per 1 SD decrease in femoral neck BMD was 2.5 for women and 3.0 for men [12]. However, the standard deviation for subjects 570 years of age, in whom most hip fractures occur, was substantially greater in the men (0.141–0.143 g/cm) than the women (0.128–0.130 g/ cm) in Rotterdam. By contrast, the Rochester analysis employed standard deviations from normal 20to 29year-old subjects, and these happened to be less in men than women at the femoral neck (0.109 g/cm vs 0.119 g/ cm). Thus, sex-specific fracture risks per 1 SD change are partly dependent upon the size of the standard deviations, and it appears that the studies which found equivalent sex-specific relative risks all used larger standard deviations for men than for women when making the calculations. The use of different standard deviations may therefore confound direct comparisons of men and women, but these relative risks can be difficult to interpret and they are not closely correlated with absolute fracture risk in any event [14]; the latter (see next) may be more relevant clinically. Data also exist which show that absolute fracture risk is comparable in women and men who have the same BMD level. In the Hawaii Osteoporosis Study, for example, the incidence of new morphometric vertebral fractures over 6–10 years of follow-up was the same for women and men with a given calcaneus BMD (Fig. 1) and similar results were seen at the distal forearm [10]. The risk of fractures generally over 5 years of follow-up was also practically identical among elderly Finnish men and women who had the same size-adjusted calcaneus BMD level, although women were likely to experience a greater number of fractures [15]. Similarly, when fracture risk was estimated from baseline femoral neck BMD in the Rotterdam study, annual hip fracture incidence over Osteoporos Int (2001) 12:707–709 2001 International Osteoporosis Foundation and National Osteoporosis Foundation Osteoporosis International

Osteoporosis in men.

Osteoporosis is characterized by bone loss with microarchitectural deterioration, reduced bone strength, and increased risk of fracture (Kanis et al., J Bone Miner Res 9:1137–41, 1994; NIH Consensus Development Panel on Osteoporosis Prevention, South Med J 94:569–73, 2001). It is, in part, a disorder of the aging skeleton and, thus, as the world population ages, it is inevitable that the incidence of this disease will also increase. For example, in the USA during the first quarter of this century, the population greater than 50 years old will increase by 60 % (Day, Population projections of the USA by age, sex, race, and hispanic origin: 1995 to 2050. US Bureau of the Census, Current Population Reports, US Government Printing Office, Washington, DC, P25-1130, 1996; Cummings and Melton, Lancet 359:1761–7, 2002). With that increase in the older population will come a greater incidence of osteoporosis. This disease has traditionally been considered to be a disease of postmenopausal women but men now constitute nearly 1/4 of all osteoporotic patients (Burge et al., J Bone Miner Res 22(3):465–75, 2007; Center et al., JAMA 297:387–94, 2007). Hip fracture, which accounts for at least 1/3 of all fractures in men (Gullberg et al., Osteoporos Int 7:407–13, 1997), is associated with a threefold higher mortality rate in men than in women (Center et al., Lancet 353:878–82, 1999). Data from Trombetti et al. (Osteoporos Int. 13:731–7, 2002) show that more years of life are lost in men than in women after a hip fracture. This may be due, at least in part, to the impression that men are typically older when they sustain a hip fracture and are, therefore, more likely to suffer from serious comorbid events when they fracture. Data from the classic study of Johnell and Kanis (Osteoporos Int 17:1726–33, 2006), however, indicates that worldwide, the peak number of hip fractures occurs at a similar age for men and women, between the ages of 75 and 79.

Determinants of peak bone mass and mechanisms of bone loss.

Peak bone mass (PBM) is defined as the amount of bony tissue present at the end of skeletal maturation [1]. Bone strength is mainly determined by volumetric density, i.e., the amount of bony tissue per unit of volume, by outer bone dimensions, by intraosseous microarchitecture, and by intrinsic bone quality [2]. The contribution of bone size to strength is illustrated by the recent observation that for matched vertebral height and volumetric density, patients with vertebral fracture have smaller crosssectional vertebral body area than nonfractured subjects [3]. Before puberty, no consistent gender difference in bone mass of axial or appendicular skeleton has been reported [4–6]. Furthermore, there is no evidence for a gender difference in bone mass at birth. Likewise, the volumetric bone mineral density (BMD) appears to be similar among female and male newborns [7]. This absence of gender difference in bone mass is maintained until the onset of pubertal maturation [8–10]. During puberty, bone mineral mass more than doubles in skeletal sites such as the lumbar spine [6,11]. This increase occurs approximately 2 years later in males than females. Then, a gender difference in bone mass is expressed. In addition to a possible late prepubertal increased value due to the 2-year delay in the onset of pubertal maturation in males, this difference appears to result essentially from a more prolonged bone growth period in males than females, with a larger increase in bone size and in cortical thickness [12]. During puberty, the accumulation rate in areal BMD at both the lumbar spine and femoral neck levels increases over a 3or 4year period in females and males, respectively [11]. The change in bone mass accumulation rate is less marked in the long bone diaphyses. Puberty affects bone size much more than volumetric BMD (Fig. 1). There is no significant gender difference in the volumetric trabecular density at the end of pubertal maturation [8,9,13,14]. However, blacks have greater volumetric density than whites [10,14]: trabecular number is similar, but the trabeculae appear to be thicker [15]. In cortical peripheral bone, there is no gender difference in the cross-sectional area of midfemoral shaft after adjustment for height and weight [13]. However, it is greater in blacks than whites for an identical cortical thickness [14]. Thus, despite the same cortical thickness, larger bones result in a greater bone mineral content. Bony tissue situated more distantly from the bone’s central axis confers a greater resistance to bending [2,16]. There is an asynchrony between the gain in statural height and bone mass growth [6,11,17]. Indeed, the peak of statural growth velocity precedes the peak of maximal bone mineral gain. In males, the greatest difference occurs in the 13–14 year age group and is more pronounced for lumbar spine and femoral neck than for midfemoral shaft [11]. In females, the largest difference occurs in the 11–12 year age group, corresponding in both genders to pubertal stages P2– P3. This phenomenon may be responsible for the occurrence of a transient relative increase in bone fragility that may account for the pattern of fracture Osteoporos Int (1999) Suppl. 2:S17–S23 s 1999 International Osteoporosis Foundation and National Osteoporosis Foundation Osteoporosis International

Severe bone pain after intravenous pamidronate in adult patients with cystic fibrosis

Osteoporosis is a recognised complication of cystic fibrosis and has been extensively reported in children and adults with the disease. 1 Gibbens TG Gilanz V Boechat MI Dufer D Carlson ME Wange CI Osteoporosis in cystic fibrosis. J Pediatr. 1988; 295: 300 Google Scholar , 2 Increased rate of fractures and severe kyphosis: sequelae of living into adulthood with cystic fibrosis. Ann Intern Med. 1998; 128: 186-193 Crossref PubMed Scopus (254) Google Scholar The pathogenesis of low bone density and optimum therapeutic strategies to improve it are currently undefined. We describe our preliminary experience with intravenous (iv) pamidronate in the treatment of low bone density in adults with cystic fibrosis. Currently, its use in this patient group is unreported, but iv pamidronate is an effective treatment for patients with postmenopausal osteoporosis and corticosteroid-induced osteoporosis. 3 Two years' effectiveness of intravenous parmidronate (APD) versus oral fluoride for osteoporosis occuring in the menopause. Osteoporos Int. 1994; 4: 76-83 Crossref PubMed Scopus (100) Google Scholar , 4 Intravenous pamidronate in the treatment of osteoporosis associated with corticosteroid dependent lung disease: an open pilot study. Thorax. 1992; 47: 932-936 Crossref PubMed Scopus (78) Google Scholar