Jackie A. Clowes

The role of the immune system in the pathophysiology of osteoporosis.

Summary:  The role of the immune system in the development of senile osteoporosis, which arises primarily through the effects of estrogen deficiency and secondary hyperparathyroidism, is slowly being unraveled. This review focuses on our current understanding of how the components of this complex‐interlinked system are regulated and how these fit with previous models of senile and postmenopausal osteoporosis. There is certainly substantial evidence that bone remodeling is a tightly regulated, finely balanced process influenced by subtle changes in proinflammatory and inhibitory cytokines as well as hormones and cellular components that act primarily but not exclusively through the receptor activator of nuclear factor‐κB (RANK)/RANK ligand/osteoprotegerin system. In addition, an acute or chronic imbalance in the system due to infection or inflammation could contribute to systemic (or local) bone loss and increase the risk of fracture. Although significant progress has been made, there remains much to be done in unraveling this complex interaction between the immune system and bone.

Regulation of circulating sclerostin levels by sex steroids in women and in men

Sex steroids are important regulators of bone turnover, but the mechanisms of their effects on bone remain unclear. Sclerostin is an inhibitor of Wnt signaling, and circulating estrogen (E) levels are inversely associated with sclerostin levels in postmenopausal women. To directly test for sex steroid regulation of sclerostin levels, we examined effects of E treatment of postmenopausal women or selective withdrawal of E versus testosterone (T) in elderly men on circulating sclerostin levels. E treatment of postmenopausal women (n = 17) for 4 weeks led to a 27% decrease in serum sclerostin levels [versus +1% in controls (n = 18), p < .001]. Similarly, in 59 elderly men, we eliminated endogenous E and T production and studied them under conditions of physiologic T and E replacement, and then following withdrawal of T or E, we found that E, but not T, prevented increases in sclerostin levels following induction of sex steroid deficiency. In both sexes, changes in sclerostin levels correlated with changes in bone‐resorption, but not bone‐formation, markers (r = 0.62, p < .001, and r = 0.33, p = .009, for correlations with changes in serum C‐terminal telopeptide of type 1 collagen in the women and men, respectively). Our studies thus establish that in humans, circulating sclerostin levels are reduced by E but not by T. Moreover, consistent with recent data indicating important effects of Wnts on osteoclastic cells, our findings suggest that in humans, changes in sclerostin production may contribute to effects of E on bone resorption.

Potential Role of Pancreatic and Enteric Hormones in Regulating Bone Turnover

ADEQUATE NUTRIENT INTAKE and normal gastrointestinal function are essential to bone health. Disorders of nutrient supply caused by either abnormal intake (e.g., anorexia nervosa, starvation) or absorption (e.g., celiac disease, inflammatory bowel disease) may lead to bone disease and an increased fracture risk. The majority of studies examining the effects of nutrients on bone turnover have focused on well-established nutrients (e.g., calcium and phosphate) and homeostatic regulators (e.g., PTH and vitamin D). Three recent observations have suggested the potential involvement of alternative mechanisms regulating the interaction between nutrition and bone turnover. First, bone turnover has a marked circadian rhythm (∼100%), with higher bone resorption at night. The mechanism regulating this rhythm seems to be partially related to the cyclical intake of nutrients. Second, there is an acute suppression of bone resorption in vivo (∼50%), which occurs within hours of the ingestion of a mixed meal, glucose, protein, or calcium. Third, in a rodent model, providing the normal diet in multiple small fractions decreased bone resorption measured using [H]tetracycline excretion and increased BMD compared with a matched nutrient load given once a day. These studies suggest acute changes in dietary intake or the pattern of nutrient intake may have an impact on bone homeostasis. This article reviews the evidence supporting an acute nutrient-induced regulation of bone homeostasis, discusses the potential mechanisms involved, and speculates on the possible evolutionary advantage this may confer on animals that have an intermittent supply (or intake) of nutrients.

Use of DXA-Based Structural Engineering Models of the Proximal Femur to Discriminate Hip Fracture

Several DXA‐based structural engineering models (SEMs) of the proximal femur have been developed to estimate stress caused by sideway falls. Their usefulness in discriminating hip fracture has not yet been established and we therefore evaluated these models. The hip DXA scans of 51 postmenopausal women with hip fracture (30 femoral neck, 17 trochanteric, and 4 unspecified) and 153 age‐, height‐, and weight‐matched controls were reanalyzed using a special version of Hologics software that produced a pixel‐by‐pixel BMD map. For each map, a curved‐beam, a curved composite‐beam, and a finite element model were generated to calculate stress within the bone when falling sideways. An index of fracture risk (IFR) was defined over the femoral neck, trochanter, and total hip as the stress divided by the yield stress at each pixel and averaged over the regions of interest. Hip structure analysis (HSA) was also performed using Hologic APEX analysis software. Hip BMD and almost all parameters derived from HSA and SEM were discriminators of hip fracture on their own because their ORs were significantly >1. Because of the high correlation of total hip BMD to HSA and SEM‐derived parameters, only the bone width discriminated hip fracture independently from total hip BMD. Judged by the area under the receiver operating characteristics curve, the trochanteric IFR derived from the finite element model was significant better than total hip BMD alone and similar to the total hip BMD plus bone width in discriminating all hip fracture and femoral neck fracture. No index was better than total hip BMD for discriminating trochanteric fractures. In conclusion, the finite element model has the potential to replace hip BMD in discriminating hip fractures.

Comparison of Densitometric and Radiographic Vertebral Fracture Assessment Using the Algorithm‐Based Qualitative (ABQ) Method in Postmenopausal Women at Low and High Risk of Fracture

Using ABQ diagnosis, the sensitivity to detect VF of densitometric versus radiographic assessment in 755 postmenopausal women was 71‐81% and specificity was 97%. Misdiagnosis was influenced by image quality and was more common for mild deformities.

The effect of cessation of raloxifene treatment on bone turnover in postmenopausal women

There is evidence to suggest accelerated bone loss following estrogen cessation. The effect of cessation of raloxifene therapy on bone turnover is unknown. Our aim was to determine the effect of cessation of raloxifene treatment on bone turnover and bone mineral density (BMD) in postmenopausal, osteopenic women. Women aged 50 to 80 years received raloxifene for 96 weeks and were then randomized to continue raloxifene (group 1, n=20) or placebo (group 2, n=20) for a further 96 weeks. A third group (group 3, n=14) received no treatment. Bone turnover markers and bone density (BMD) were measured throughout the study. Raloxifene treatment for 96 weeks resulted in a decrease in bone turnover (PINP by 31%) and an increase in spine BMD (by 2%) but no change in hip BMD for groups 1 and 2. Continuation of raloxifene (group 1) maintained these changes. Following cessation of raloxifene (group 2), bone markers returned to baseline levels (by 120 weeks). Hip BMD was decreased by 2% at 192 weeks compared to baseline. Bone markers in the controls (group 3) remained at the upper limit of the reference range throughout, with decreases in BMD of 2.3% (spine) and 2.8% (hip). Bone loss following cessation of raloxifene therapy at 96 weeks was greater than in the control group, suggesting accelerated bone loss. The beneficial effect on bone turnover of 96 weeks of raloxifene was lost 6 months after cessation of treatment.

Performance of Quantitative Ultrasound Measurements of Bone for Monitoring Raloxifene Therapy

Raloxifene increases bone mineral density (BMD) and decreases vertebral fracture risk; the effects on quantitative ultrasound (QUS) variables, however, have been less well studied. We aimed to further evaluate the effectiveness of QUS for monitoring raloxifene treatment and withdrawal effects. Osteopenic, postmenopausal women (age=50-80 yr, n=125), who completed a 96-wk study (phase A) evaluating treatment compliance or monitoring, were invited to participate in a 96-wk raloxifene withdrawal study (phase B). Those originally receiving treatment were then randomized to continue on raloxifene (60 mg/d)+calcium (500 mg/d) (n=23) or to discontinue raloxifene and take placebo+calcium (500 mg/d) (n=23). Previously untreated women remained untreated (n=12). Yearly QUS and BMD measurements were performed. At the end of phase A, lumbar spine BMD (p=0.005), amplitude-dependent speed of sound (Ad-SoS) (p=0.006) and average SoS (p=0.040) decreased in untreated women but remained stable in treated women. Significant changes in Ad-SoS and ultrasonic bone profiler index had occurred in treated women by the end of phase B (p<0.01). All variables, except bone transmission time, were higher for those receiving any raloxifene treatment (p<0.05). Until further knowledge has been acquired, QUS measurement variables should only be used in conjunction with BMD when assessing changes in bone because of raloxifene therapy.

Device-specific thresholds to diagnose osteoporosis at the proximal femur: an approach to interpreting peripheral bone measurements in clinical practice: Reply to comment by Pluskiewicz and Drozdzowska

Dear Editor, Dr. Pluskiewicz and Dr. Drozdzowska raise two important points relating to the interpretation of peripheral densitometry measurements in clinical practice which we believe are worthy of comment. Firstly, we selected total hip BMD rather then femoral neck BMD as the latter measurement site is subject to substantially greater variability, which makes it a less robust site for classifying an individual. Furthermore, minimizing variability is important not only for diagnosis but also when monitoring response to therapy and total hip BMD is generally regarded as the optimum measurement site in clinical practice [1]. Secondly, our study confirmed that a single T-score criterion cannot be universally applied to different peripheral bone measurement devices. We established that peripheral densitometry devices can be interpreted using two thresholds determined from total hip BMD which would identify individuals with 95% sensitivity or 95% specificity who require (1) treatment or (2) no treatment based on a peripheral measurement alone or (3) require additional central densitometry measurements [2]. We presented the thresholds for nine different types of peripheral devices and eight different measurement sites; however Dr Pluskiewicz et al. rightly point out that the Achilles+ provides data as a stiffness index (SI). In order to provide physicians with a practical approach to the interpretation of the Achilles+ data in clinical practice, we have calculated the SI using the manufacturer_s formula as follows; SI=(0.28* Achilles SOS) + (0.67*Achilles BUA) −420. Using this formula, the threshold above which we are 95% certain an individual did not have osteoporosis (95% sensitivity) compared to total hip BMD (T-score<−2.5)=80.5. The threshold below which we are 95% certain an individual had osteoporosis (95% specificity) compared to total hip BMD (T-score<−2.5)=59.1. Wewould like to thank Drs. Pluskiewicz and Drozdzowska for raising these two important and practical points relating to the interpretation of our data in clinical practice.