Kenneth Eric Poole

Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation

Osteocytes are the most abundant cells in bone and are ideally located to influence bone turnover through their syncytial relationship with surface bone cells. Osteocyte‐derived signals have remained largely enigmatic, but it was recently reported that human osteocytes secrete sclerostin, an inhibitor of bone formation. Absent sclerostin protein results in the high bone mass clinical disorder sclerosteosis. Here we report that within adult iliac bone, newly embedded osteocytes were negative for sclerostin staining but became positive at or after primary mineralization. The majority of mature osteocytes in mineralized cortical and cancellous bone was positive for sclerostin with diffuse staining along dendrites in the osteocyte canaliculi. These findings provide for the first time in vivo evidence to support the concept that osteocytes secrete sclerostin after they become embedded in a mineralized matrix to limit further bone formation by osteoblasts. Sclerostin did not appear to influence the formation of osteocytes. We propose that sclerostin production by osteocytes may regulate the linear extent of formation and the induction or maintenance of a lining cell phenotype on bone surfaces. In doing so, sclerostin may act as a key inhibitory signal governing skeletal microarchitecture.

Reduced Vitamin D in Acute Stroke

Background and Purpose— Stroke leads to a reduction in bone mineral density, altered calcium homeostasis, and an increase in hip fractures. Vitamin D deficiency is well documented in long-term stroke survivors and is associated with post-stroke hip fractures. Less is known regarding levels in acute stroke. Methods— We compared the serum 25-dihydroxyvitamin D levels of 44 patients admitted to an acute stroke unit with first-ever stroke with results obtained by measuring 96 healthy ambulant elderly subjects every 2 months for 1 year. Statistical Z scores of serum vitamin D were then calculated after seasonal adjustment for the month of sampling. Results— The mean Z score of vitamin D in acute stroke was −1.4 SD units (95% CI, −1.7, −1.1), with 77% of patients falling in the insufficient range. Conclusions— Reduced vitamin D was identified in the majority of patients with acute stroke throughout the year and may have preceded stroke. Vitamin D is a potential risk marker for stroke, and the role of vitamin D repletion in enhancing musculoskeletal health after stroke needs to be explored.

Osteoporosis and its management

Fractures caused by osteoporosis affect one in two women and one in five men over the age of 50, resulting in an estimated annual cost to the health services of around £1.8bn (€2.7bn;

High resolution cortical bone thickness measurement from clinical CT data

3.5bn) in the United Kingdom and €30bn in all of Europe.1 2 Most patients with osteoporosis are managed in primary care, but a minority will benefit from referral to specialised centres. In recent years considerable advances have been made both in the identification of people at high risk of fracture and in therapeutic options to reduce the risk of fracture. This review focuses on these areas and also on the partnership that is required between primary and secondary care to optimise the management of patients with osteoporosis. Osteoporosis results from reduced bone mass and disruption of the micro-architecture of bone (fig 1)⇓, giving decreased bone strength and increased risk of fracture, particularly of the spine, hip, wrist, humerus, and pelvis. The risk of fractures increases steeply with age (fig 2)⇓ and most of those affected are over 75.1 2 Globally, osteoporotic fractures caused an estimated 5.8 million disability adjusted life years in the year 2000w1 and are also associated with increased mortality. Hip fractures (fig 3)⇓ result in loss of independence for at least a third of people with osteoporosis, and vertebral fractures (fig 4)⇓ cause height loss, chronic pain, and difficulty with normal daily activities. Fig 1 Scanning electron micrographs to show the structure of L3 vertebra in a 31 year old woman (top) and in a 70 year old woman (bottom). Note that many of the plate-like structures have become converted to thin rods Fig 2 Epidemiology of osteoporotic fractures in men and women. Reprinted with permission28 Fig 3 Fracture of the femoral neck Fig 4 …

Falls, fractures, and osteoporosis after stroke: time to think about protection?

The distribution of cortical bone in the proximal femur is believed to be a critical component in determining fracture resistance. Current CT technology is limited in its ability to measure cortical thickness, especially in the sub-millimetre range which lies within the point spread function of today’s clinical scanners. In this paper, we present a novel technique that is capable of producing unbiased thickness estimates down to 0.3 mm. The technique relies on a mathematical model of the anatomy and the imaging system, which is fitted to the data at a large number of sites around the proximal femur, producing around 17,000 independent thickness estimates per specimen. In a series of experiments on 16 cadaveric femurs, estimation errors were measured as −0.01 ± 0.58 mm (mean ± 1 std.dev.) for cortical thicknesses in the range 0.3–4 mm. This compares with 0.25 ± 0.69 mm for simple thresholding and 0.90 ± 0.92 mm for a variant of the 50% relative threshold method. In the clinically relevant sub-millimetre range, thresholding increasingly fails to detect the cortex at all, whereas the new technique continues to perform well. The many cortical thickness estimates can be displayed as a colour map painted onto the femoral surface. Computation of the surfaces and colour maps is largely automatic, requiring around 15 min on a modest laptop computer.

Distribution of cortical bone in the femoral neck and hip fracture: a prospective case-control analysis of 143 incident hip fractures; the AGES-REYKJAVIK Study.

Background— Osteoporosis is a significant complication of stroke. The clinical course of hemiplegic stroke predisposes patients to disturbed bone physiology. Sudden immobility and unilateral loss of function unload the skeleton at key areas such as the affected hip. This is manifest by an early reduction in bone density at this site. Stroke patients may also have motor, sensory, and visual/perceptual deficits that predispose them to falls. These factors result in an early but sustained increase in hip fractures after stroke. Summary of Comment— Potential bone loss is often overlooked in stroke treatment. Morbidity and mortality from hip fractures might be reduced by preventing bone loss at an early stage. In the crucial first year after stroke, bone loss seems to be due to accelerated resorption. Bisphosphonates are the drugs of choice in preventing osteoclastic bone resorption, but oral administration soon after stroke may be impractical. Potent new intravenous bisphosphonates have been used in postmenopausal women with osteoporosis with good preliminary results. Effective dosing regimens for osteoporosis have included a single annual or semiannual injection of bisphosphonate as well as weekly oral dosing. This article reviews the current literature on osteoporosis and hip fractures after stroke, making a case for a trial of intravenous bisphosphonates early after stroke. Conclusions— Hip fracture after stroke is an increasingly recognized problem. Measures to prevent bone loss and preserve bone architecture have not been part of stroke management thus far. Because rapid bone loss is a risk factor for fracture, we believe that a randomized, placebo-controlled trial of intravenous bisphosphonates given in the early phase of stroke rehabilitation is indicated.

Cortical Thickness Mapping to Identify Focal Osteoporosis in Patients with Hip Fracture

In this prospective nested case-control study we analyzed the circumferential differences in estimated cortical thickness (Est CTh) of the mid femoral neck as a risk factor for osteoporotic hip fractures in elderly women and men. Segmental QCT analysis of the mid femoral neck was applied to assess cortical thickness in anatomical quadrants. The superior region of the femoral neck was a stronger predictor for hip fracture than the inferior region, particularly in men. There were significant gender differences in Est CTh measurements in the control group but not in the case group. In multivariable analysis for risk of femoral neck (FN) fracture, Est CTh in the supero-anterior (SA) quadrant was significant in both women and men, and remained a significant predictor after adjustment for FN areal BMD (aBMD, dimensions g/cm², DXA-like), (p=0.05 and p<0.0001, respectively). In conclusion, Est CTh in the SA quadrant best discriminated cases (n=143) from controls (n=298), especially in men. Cortical thinning superiorly in the hip might be of importance in determining resistance to fracture.

Femoral neck trabecular bone: loss with aging and role in preventing fracture.

Background Individuals with osteoporosis are predisposed to hip fracture during trips, stumbles or falls, but half of all hip fractures occur in those without generalised osteoporosis. By analysing ordinary clinical CT scans using a novel cortical thickness mapping technique, we discovered patches of markedly thinner bone at fracture-prone regions in the femurs of women with acute hip fracture compared with controls. Methods We analysed CT scans from 75 female volunteers with acute fracture and 75 age- and sex-matched controls. We classified the fracture location as femoral neck or trochanteric before creating bone thickness maps of the outer ‘cortical’ shell of the intact contra-lateral hip. After registration of each bone to an average femur shape and statistical parametric mapping, we were able to visualise and quantify statistically significant foci of thinner cortical bone associated with each fracture type, assuming good symmetry of bone structure between the intact and fractured hip. The technique allowed us to pinpoint systematic differences and display the results on a 3D average femur shape model. Findings The cortex was generally thinner in femoral neck fracture cases than controls. More striking were several discrete patches of statistically significant thinner bone of up to 30%, which coincided with common sites of fracture initiation (femoral neck or trochanteric). Interpretation Femoral neck fracture patients had a thumbnail-sized patch of focal osteoporosis at the upper head-neck junction. This region coincided with a weak part of the femur, prone to both spontaneous ‘tensile’ fractures of the femoral neck, and as a site of crack initiation when falling sideways. Current hip fracture prevention strategies are based on case finding: they involve clinical risk factor estimation to determine the need for single-plane bone density measurement within a standard region of interest (ROI) of the femoral neck. The precise sites of focal osteoporosis that we have identified are overlooked by current 2D bone densitometry methods.

Imaging the femoral cortex: Thickness, density and mass from clinical CT

Hip fracture risk rises 100‐ to 1000‐fold over six decades of age, but only a minor part of this increase is explained by declining BMD. A potentially independent cause of fragility is cortical thinning predisposing to local crushing, in which bone tissues material disintegrates at the microscopic level when compressed beyond its capacity to maintain integrity. Elastic instability or buckling of a much thinned cortex might alternatively occur under compression. In a buckle, the cortex moves approximately at right angles to the direction of load, thereby distorting its microstructure, eventually to the point of disintegration. By resisting buckling movement, trabecular buttressing would protect the femoral neck cortex against this type of failure but not against crushing. We quantified the effect of aging on trabecular BMD in the femoral neck and assessed its contribution to cortical elastic stability, which determines resistance to buckling. Using CT, we measured ex vivo the distribution of bone in the midfemoral necks of 35 female and 33 male proximal femurs from cases of sudden death in those 20–95 yr of age. We calculated the critical stress σcr, at which the cortex was predicted to buckle locally, from the geometric properties and density of the cortical zone most highly loaded in a sideways fall. Using long‐established engineering principles, we estimated the amount by which stability or buckling resistance was increased by the trabecular bone supporting the most stressed cortical sector in each femoral neck. We repeated these measurements and calculations in an age‐ and sex‐matched series of femoral necks donated by women who had suffered intracapsular hip fracture and controls, using histological measurements of cortical thickness to improve accuracy. With normal aging, trabecular BMD declined asymmetrically, fastest in the supero‐lateral one‐half (in antero‐posterior projection) of the trabecular compartment. When viewed axially with respect to the femoral neck, the most rapid loss of trabecular bone occurred in the posterior part of this region (supero‐posterior [S‐P]), amounting to a 42% reduction in women (34% in men) over five decades of adult age. Because local cortical bone thickness declined comparably, age had no significant effect on the relative contributions of cortical and trabecular bone to elastic stability, and trabecular bone was calculated to contribute 40% (in men) and 43% (in women) to the S‐P cortex of its overall elastic stability. Hip fracture cases had reduced elastic stability compared with age‐matched controls, with a median reduction of 49% or 37%, depending on whether thickness was measured histologically or by CT (pQCT; p < 0.002 for both). This effect was because of reduced cortical thickness and density. Trabecular BMD was similar in hip fracture cases and controls. The capacity of the femur to resist fracture in a sideways fall becomes compromised with normal aging because cortical thickness and trabecular BMD in the most compressed part of the femoral neck both decline substantially. This decline is relatively more rapid than that of femoral neck areal BMD. If elastic instability rather than cortical crushing initiates the fracture event, interventions that increase trabecular bone in the proximal femur have great potential to reduce fracture risk because the gradient defining the increase in elastic stability with increasing trabecular BMD is steep, and most hip fracture cases have sufficient trabecular bone for anabolic therapies to build on.

Hypovitaminosis D among rheumatology outpatients in clinical practice

Highlights ► Focal thinning of cortical bone in the proximal femur predisposes a hip to fracture. ► Thinning is difficult to detect in CT since the cortex may be narrower than the PSF. ► We present a model-fitting technique to estimate cortical thickness, density and mass. ► Evaluation on cadaveric femurs confirms accurate measurement of mass and peak density. ► Thickness errors do not exceed 20% and are confined to regions of thin cortex.