Beyond hip: importance of other nonspinal fractures.

It is widely accepted that hip and spine fractures are associated with substantial morbidity, but there is growing awareness that other fractures are under-recognized. The incidence of nonspinal, nonhip fractures is higher than for hip fractures because they occur at an earlier age. Furthermore, the incidence of nonspinal, nonhip fractures exceeds that of hip fractures in men and women >80 years old. Nonspinal, nonhip fractures are associated with considerable morbidity. On average, women with humeral, ankle, distal forearm, and foot fractures experience substantial numbers of limited activity days, and nonspinal, nonhip fractures account for almost a third of health care expenditures attributable to osteoporotic fractures. Nonspinal, nonhip fractures are associated with low bone mineral density, thus it may be possible to identify those at risk. Because these fractures also are indicative of increased risk at other sites, those susceptible might benefit from assessments including these other fracture types. It is the clinician's responsibility to attend to and recognize that nonspinal, nonhip fractures are usually associated with osteoporosis and should be treated.

Enhanced prediction of fracture risk combining vertebral fracture status and BMD.

UNLABELLED: Prevalent vertebral fractures are associated with increased fracture risk, but the magnitude of this effect across a range of BMD T-scores has not been quantified. In this analysis, for any given BMD T-score, incident fracture risk varied up to twelve fold when information regarding prevalent radiographic vertebral fracture status was considered. BACKGROUND: Clinical fracture risk evaluation of older women usually includes assessment of bone mineral density (BMD) but often not vertebral fracture status. In this analysis, we quantified the impact of vertebral fracture burden on two year fracture risk across a range of BMD T-scores. METHODS: Data were from 2,651 postmenopausal women who were assigned to the placebo groups of the Fracture Prevention Trial (median observation 21 months) and the Multiple Outcomes of Raloxifene Evaluation Trial (MORE; observation 2 years). Using the Genant visual semiquantitative criteria, we defined prevalent vertebral fracture status as: a) presence or absence of fracture; b) fracture number; c) maximum semi-quantitative (SQ) score (normal=0, mild fracture=1, moderate fracture=2, severe fracture=3); and d) spinal deformity index (SDI) score (sum of SQ scores of T4 to L4 vertebrae). Incident fractures over two years were identified via lateral spine radiographs and outside the spine by questioning of patients and review of radiographs or radiographic reports. RESULTS: Femoral neck BMD T-score provided significant information regarding fracture risk. Across the range of T-scores, vertebral fracture status provided additional prognostic information. The risk increased with increasing number and severity of prevalent vertebral fractures and SDI, a summary measure of spine fracture burden. Across a range of BMD values, prevalent spine fracture burden as assessed by SDI increased the risk of incident vertebral fractures by up to 12-fold, nonvertebral fractures by about twofold, and any fractures by up to sevenfold. CONCLUSIONS: These findings indicate that at any given BMD T-score, the risk of incident vertebral, non-vertebral, and any fracture depended heavily on prevalent radiographic vertebral fracture status. Assessment of vertebral fracture status, in addition to BMD, provides practical and relevant clinical information to aid in predicting fracture risk in postmenopausal women.

Teriparatide in postmenopausal women with osteoporosis and mild or moderate renal impairment.

INTRODUCTION: The prevalence of both osteoporosis and renal impairment increases with age. METHODS: Using data from the Fracture Prevention Trial, the safety and efficacy of teriparatide [rhPTH(1-34)] in postmenopausal women with osteoporosis and renal impairment were explored. Patients were required to have serum creatinine concentrations < or =2.0 mg/dl and normal serum parathyroid hormone (PTH) concentrations and were randomized to receive daily subcutaneous injections of placebo or teriparatide 20 or 40 mcg/day. Glomerular filtration rate (GFR) was estimated using the Cockcroft-Gault equation. Patients were defined from baseline assessments to have normal (GFR > or =80 ml/min), mildly impaired (GFR 50-79 ml/min), or moderately impaired (GFR 30-49 ml/min) renal function for bone mineral density (BMD) and amino-terminal extension peptide of procollagen type 1 (PINP) analyses, and normal (GFR > or =80 ml/min) or impaired (GFR <80 ml/min) renal function for fracture analyses. RESULTS AND CONCLUSIONS: Compared with patients with normal renal function, patients with renal impairment were older, shorter, weighed less, had been postmenopausal longer, and had lower baseline lumbar spine and femoral neck BMD. Compared with placebo, teriparatide significantly increased PINP and lumbar spine and femoral neck BMD within each renal function subgroup, and there was no evidence that these increases were altered by renal insufficiency (each treatment-by-subgroup interaction p>0.05). Similarly, teriparatide-mediated vertebral and nonvertebral fracture risk reductions were similar and did not differ significantly between patients with normal or impaired renal function (treatment-by-subgroup interactions p>0.05). The incidences of treatment-emergent and renal-related adverse events were consistent across treatment assignment in the normal, mildly impaired, and moderately impaired renal function subgroups. Teriparatide induced changes in mean GFR were unaffected by baseline renal function (treatment-by-renal function interaction p>0.05 for normal, mildly impaired, or moderately impaired subgroups). Patients in all renal function categories treated with teriparatide 20 or 40 mcg had an increased incidence of 4-6-h postdose serum calcium >10.6 mg/dl (the upper limit of normal) versus placebo; however, teriparatide 20 mcg/day was not associated with significantly increased incidence of 4-6-h postdose serum calcium >11 mg/dl in any renal function category. Teriparatide therapy was associated with increased incidence of elevated uric acid, with the incidences being highest in patients with moderately impaired renal function and in those receiving teriparatide 40 mcg/day. Even so, adverse event data did not suggest an increased incidence of gout or arthralgia or of nephrolithiasis events in teriparatide-treated patients with normal, mild, or moderate renal impairment.

Response rate of bone mineral density to teriparatide in postmenopausal women with osteoporosis.

PURPOSE: It is desirable for clinicians to know what bone mineral density (BMD) response they can expect in women treated with osteoporosis therapies. The focus of this analysis was to determine what percentage of women attained a lumbar spine BMD response to teriparatide that equaled or exceeded the least significant change (LSC) value of 3%. METHODS: Data from three clinical trials involving postmenopausal women with osteoporosis were examined. The Fracture Prevention Trial was a double-blinded, placebo-controlled clinical trial examining the safety and efficacy of teriparatide 20 and 40 microg/day. The other two trials were double-blinded, head-to-head comparisons of alendronate 10 mg/day and teriparatide 20 or 40 microg/day, respectively. Only treatment-compliant women who had lumbar spine BMD measurements at all specified time points in these trials were included. For reference, we also examined the percentage of women with lumbar spine BMD responses to alendronate. Hip BMD responses that equaled or exceeded 3% were also examined. RESULTS: According to the LSC criteria, 91% of the teriparatide 20 microg/day group and 94% of the teriparatide 40 microg/day group were lumbar spine BMD responders at 18 months in the Fracture Prevention Trial. In the teriparatide 20 microg/alendronate head-to-head trial, 94% of women receiving teriparatide had a lumbar spine BMD response that equaled or exceeded the 3% criterion at 18 months compared to 75% of those receiving alendronate 10 mg/day (p < 0.01). In the teriparatide 40 microg/day group of the other head-to-head trial, 92% of women achieved the 3% criterion for the lumbar spine at 12 months compared to 69% of those receiving alendronate 10 mg/day (p < 0.01). The median 3-month change in amino-terminal extension peptide of procollagen type 1 [PINP] in women who had a lumbar spine BMD response to teriparatide at 18 months was larger than in women who did not have a lumbar spine BMD response. However, the median 3-month PINP change in lumbar spine BMD nonresponders still exceeded the LSC value of 10 microg/L. Although the percentage of teriparatide-treated women with a hip BMD response that met the 3% criterion was significantly greater than for placebo, there was no significant difference between the percentage of teriparatide 20 microg/day and alendronate 10 mg/day responders in the comparison trial. The baseline characteristics of teriparatide lumbar spine responders and nonresponders were similar. CONCLUSION: This analysis demonstrates that the vast majority of treatment-compliant postmenopausal women with osteoporosis and minimal prior bisphosphonate exposure have a lumbar spine BMD response to teriparatide that meets or exceeds the LSC. The characteristics of teriparatide responders and nonresponders were not significantly different; thus, we were unable to discern any characteristics that could be used to identify potential nonresponders.

Fracture risk reduction during treatment with teriparatide is independent of pretreatment bone turnover.

INTRODUCTION: Teriparatide is a bone formation agent that increases bone turnover and mass, resulting in an increase in bone strength and a decrease in fracture risk. METHODS: The primary purpose of this analysis was to evaluate the association between pretreatment bone turnover marker (BTM) concentrations and the absolute and relative fracture risks after adjusting for baseline femoral neck BMD, number of prevalent vertebral fractures, and age. Because femoral neck BMD is commonly attained in the assessment of patients at risk for osteoporosis, we examined the ability of a multivariate assessment including pretreatment BTM concentration and femoral neck BMD to predict future fracture risk after adjusting for the number of prevalent vertebral fractures. We examined data from the Fracture Prevention Trial, a study designed to determine the effect of teriparatide 20 mcg/day and teriparatide 40 mcg/day on vertebral and nonvertebral fracture risk in postmenopausal women with osteoporosis. BTM were analyzed in two subsets of women within the Fracture Prevention Trial, and included serum bone-specific alkaline phosphatase (BSAP), serum carboxy-terminal extension peptide of procollagen type I (PICP), serum amino-terminal extension peptide of procollagen type I (PINP), urinary free deoxypyridinoline (DPD), and urinary N-terminal telopeptide (NTX). RESULTS: Teriparatide significantly reduced the risk of fracture [four BTM subset (n = 520), placebo = 14.3%, teriparatide = 5.8%, P < 0.05; PINP subset (n = 771), placebo = 17.7%, teriparatide = 5.5%, P < 0.05]. Subjects with the highest pretreatment BTM concentrations had the greatest fracture risk. Teriparatide-mediated absolute risk reduction was greatest for women with high pretreatment bone turnover; however, the relative fracture risk reduction was independent of pretreatment bone turnover. After adjusting for pretreatment BTM and number of prevalent vertebral fractures, baseline femoral neck BMD was not a significant predictor of fracture risk. CONCLUSION: Teriparatide-mediated relative fracture risk reduction was independent of pretreatment bone turnover, demonstrating that this therapy offers clinical benefit to patients across a range of disease severity.

A simple method for determining the probability a new vertebral fracture is present in postmenopausal women with osteoporosis.

The vertebral fracture status of women with osteoporosis has strong prognostic implications that may influence clinical decisions. We developed a simple method for estimating the probability that a new vertebral fracture has occurred in postmenopausal women with osteoporosis. Data was from the placebo groups of the Fracture Prevention Trial (median observation =21 months) and the MORE Trial at 2 years. A logistic regression analysis identified prior vertebral fracture (yes/no), new or worsening back pain (yes/no), and height loss (> or =2 cm, yes/no) as significant predictors for the presence of a new vertebral fracture. The actual probability of a new vertebral fracture in patients without these predictors, over the median observation period of 23 months, was 2.1%. Presence of back pain increased this probability fourfold; prior vertebral fracture increased this probability threefold, and height loss > or =2 cm increased this probability threefold. The predicted probabilities of a new vertebral fracture being present for each subgroup representing each of the eight possible combinations of back pain, prior vertebral fracture, and height loss were highly correlated with both the multivariate logistic regression-derived probabilities (r=0.98, p <0.001) and with the actual probabilities (r=0.99, p <0.001). The validity of this simple method was confirmed in patients from the MORE trial at both 2 years and 3 years, and in the Fracture Prevention Trial alone. This simple method provides clinicians with an estimate of the probability that a new vertebral fracture has occurred in postmenopausal women with osteoporosis.

Attenuated agonist evoked vasoconstrictor responses in the perfused mesenteric vascular bed of streptozotocin diabetic rats.

We compared agonist-evoked responses in the perfused mesenteric vascular bed (MVB) of streptozotocin (STZ) diabetic Sprague-Dawley rats 2 and 14 weeks after induction of diabetes. Endothelin-1 (ET-1)-, methoxamine (MTX)-, and KCl-evoked vasoconstrictor responses were unchanged in 2-week-old diabetic rats. In contrast, both the sensitivity (P < 0.01) and the maximal vasoconstrictor responses (P < 0.05) to ET-1 were attenuated in 14-week-old diabetic rats, whereas endothelin plasma levels were increased (P < 0.05). Although no differences were observed in responses to KCl in either the 2- or 14-week-old diabetic groups, MTX-evoked maximal responses were attenuated in the 14-week-old group (P < 0.01). Changes in agonist-evoked responses in the 14-week-old diabetic group were unaffected by the protein kinase C (PKC) inhibitor, staurosporine, the phospholipase C (PLC) inhibitor, U73122, the calcium channel blocker, nifedipine, the calcium pump inhibitor, cyclopiazonic acid (CPA), or by endothelial denudation. Sodium fluoride (NaF), an activator of guanosine triphosphate binding proteins (G proteins) normalized the responses in the 14-week-old diabetic group. These data suggest that advanced stages of STZ are associated with alterations in G protein receptor coupling and/or activity leading to the attenuation of responses to vasoconstrictor agonists.

Insulin-induced biphasic responses in rat mesenteric vascular bed: role of endothelin.

The vasodilatory capacity of insulin has been widely reported, yet some investigators have not noted this effect. Because insulin has been shown to enhance endothelin release, we speculated that endothelin could be attenuating insulin-evoked vasodilation. We examined the effect of ex vivo insulin perfusion on vascular resistance by using the Sprague-Dawley rat mesenteric vascular bed. In methoxamine-preconstricted preparations, insulin (3.0 pmol/L to 10 nmol/L) evoked a concentration-dependent decrease in perfusion pressure (PP) with a maximal response of 42.0+/-9.2%, whereas continuous exposure to 10 nmol/L insulin induced a 51.8+/-3.5% relaxation. Further exposure to 10 nmol/L insulin resulted in the generation of endothelin and a subsequent loss of the vasodilatory response. Indomethacin had no effect on vascular responses. The vasodilatory response was significantly inhibited by nitric oxide synthase inhibition (20.5+/-4.2%; P<0.01) and calcium-activated potassium channel blockade (28.5+/-3.7%; P<0.05). Endothelial denudation attenuated the vasodilatory component (20.3+/-7.1%; P<0.01) and altered the biphasic pattern of the response. The decline in insulin-evoked vasodilation was significantly prevented by an endothelin-A antagonist (BQ123), an endothelin-B antagonist (BQ788), and nonselective endothelin blockade with both BQ123 and BQ788. These results demonstrate that the endothelium is intimately involved in regulating the vascular response to insulin. Insulin promotes the release of nitric oxide and endothelium-derived hyperpolarizing factor. During sustained exposure to higher concentrations, this vasodilatory effect is countered by the pathological generation of endothelin. Endothelin receptor blockade facilitates the maintenance of vasodilation despite high insulin concentrations.

Effect of sodium orthovanadate treatment on cardiovascular function in the hyperinsulinemic, insulin-resistant obese Zucker rat.

We recently demonstrated that oral vanadate treatment ameliorates exaggerated vasoconstriction in aortic tissue from the hyperinsulinemic/insulin resistant obese Zucker rat. It has been suggested that changes in large artery contractility might contribute to the development of hypertension in this strain. Thus we examined the effect of vanadate treatment (0.5 mg/ml, p.o.) on conductance and resistance vessel function as well as blood pressure (BP) in Zucker rats. Vasoconstrictor responses to endothelin-1 (ET-1) and methoxamine and vasodilator responses to acetylcholine in the aorta and perfused mesenteric vascular bed served as indices of conductance and resistance function, respectively. Separate groups were treated with insulin (12 mU/kg/min, s.c.) to determine its role in the actions of vanadate. Vanadate treatment reduced (2.5-fold; p < 0.05) elevated plasma insulin levels and abolished exaggerated aortic vasoconstriction in obese rats. Vasoconstrictor responses in the mesenteric bed, however, were similar between obese and lean rats, and were unaffected by vanadate. Vanadate did not affect elevated BP in obese rats and actually increased BP in the lean group. Insulin treatment per se failed to affect vasomotor function or BP in either strain, and acetylcholine-evoked relaxation was similar in all groups. We conclude that whereas vanadate overcomes exaggerated central artery contractility in obese Zucker rats, it fails to affect resistance vessel function or BP in this strain, and might conversely elevate BP in normotensive lean control rats. The vascular actions of vanadate in obese rats appear to occur independent of changes in plasma insulin or endothelial function.