Pierre Delmas

Alterations of Cortical and Trabecular Architecture Are Associated With Fractures in Postmenopausal Women, Partially Independent of Decreased BMD Measured by DXA: The OFELY Study

We assessed the role of low aBMD and impaired architecture—assessed by an HR‐pQCT system—in a case‐control study of postmenopausal women with fractures. Vertebral and nonvertebral fractures are associated with low volumetric BMD and architectural alterations of trabecular and cortical bone, independent of aBMD assessed by DXA.

Lasofoxifene in Postmenopausal Women with Osteoporosis

BACKGROUNDnThe effects of lasofoxifene on the risk of fractures, breast cancer, and cardiovascular disease are uncertain.nnnMETHODSnIn this randomized trial, we assigned 8556 women who were between the ages of 59 and 80 years and had a bone mineral density T score of -2.5 or less at the femoral neck or spine to receive once-daily lasofoxifene (at a dose of either 0.25 mg or 0.5 mg) or placebo for 5 years. Primary end points were vertebral fractures, estrogen receptor (ER)-positive breast cancer, and nonvertebral fractures; secondary end points included major coronary heart disease events and stroke.nnnRESULTSnLasofoxifene at a dose of 0.5 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio, 0.58; 95% confidence interval [CI], 0.47 to 0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1000 person-years; hazard ratio, 0.76; 95% CI, 0.64 to 0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; hazard ratio, 0.19; 95% CI, 0.07 to 0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; hazard ratio, 0.68; 95% CI, 0.50 to 0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41 to 0.99). Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1000 person-years; hazard ratio, 0.69; 95% CI, 0.57 to 0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.61; 95% CI, 0.39 to 0.96) Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55 to 4.58] and 2.06 [95% CI, 1.17 to 3.60], respectively). Endometrial cancer occurred in three women in the placebo group, two women in the lower-dose lasofoxifene group, and two women in the higher-dose lasofoxifene group. Rates of death per 1000 person-years were 5.1 in the placebo group, 7.0 in the lower-dose lasofoxifene group, and 5.7 in the higher-dose lasofoxifene group.nnnCONCLUSIONSnIn postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. (ClinicalTrials.gov number, NCT00141323.)

Diagnosis and management of osteoporosis in postmenopausal women: Clinical guidelines

The authors, all physicians involved in clinical research on bone and practicing clinicians, propose practical guidelines for identifying persons with osteoporosis or those at high risk of developing the disease and for managing patients who may benefit from therapy. These guidelines are based on an analysis of peer-reviewed articles published before November 1998. A flowchart of women who might benefit from treatment is provided, including clinical presentation (recent fracture of the spine, hip, or other bone or no fracture; risk factors for osteoporosis); relevant investigations (bone mineral density measurement and laboratory tests required for the differential diagnosis); and therapeutic management (general measures such as calcium and vitamin D supplementation and specific pharmacologic interventions such as estrogen, bisphosphonates, intranasal calcitonin, raloxifene, fluoride salts, and other compounds that have been assessed in randomized clinical trials). The strongest evidence for antifracture efficacy (reduction of vertebral and nonvertebral fracture risk) was observed with alendronate.

Bone Fragility: Failure of Periosteal Apposition to Compensate for Increased Endocortical Resorption in Postmenopausal Women

The increase in bone fragility after menopause results from reduced periosteal bone formation and increased endocortical resorption. Women with highest remodeling had greatest loss of bone mass and estimated bone strength, whereas those with low remodeling lost less bone and maintained estimated bone strength.

Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: The risedronate and alendronate (REAL) cohort study

IntroductionRandomized clinical trials have shown that risedronate and alendronate reduce fractures among women with osteoporosis. The aim of this observational study was to observe, in clinical practice, the incidence of hip and nonvertebral fractures among women in the year following initiation of once-a-week dosing of either risedronate or alendronate.MethodsUsing records of health service utilization from July 2002 through September 2004, we created two cohorts: women (ages 65 and over) receiving risedronate (nu2009=u200912,215) or alendronate (nu2009=u200921,615). Cox proportional hazard modeling was used to compare the annual incidence of nonvertebral fractures and of hip fractures between cohorts, adjusting for potential differences in risk factors for fractures.ResultsThere were 507 nonvertebral fractures and 109 hip fractures. Through one year of therapy, the incidence of nonvertebral fractures in the risedronate cohort (2.0%) was 18% lower (95% CI 2% – 32%) than in the alendronate cohort (2.3%). The incidence of hip fractures in the risedronate cohort (0.4%) was 43% lower (95% CI 13% – 63%) than in the alendronate cohort (0.6%). These results were consistent across a number of sensitivity analyses.ConclusionPatients receiving risedronate have lower rates of hip and nonvertebral fractures during their first year of therapy than patients receiving alendronate.

Change in Lumbar Spine BMD and Vertebral Fracture Risk Reduction in Teriparatide-Treated Postmenopausal Women With Osteoporosis†

Increases in lumbar spine BMD account for 30–41% of the vertebral fracture risk reduction with teriparatide treatment. The remaining fracture risk reduction is caused by improvements in non‐BMD determinants of bone strength.

Severity of vertebral fracture reflects deterioration of bone microarchitecture

IntroductionBone microarchitecture, a component of bone strength, is generally measured on transiliac bone biopsy samples. The objective of this study was to determine whether assessment of four grades of vertebral fracture severity could serve as a noninvasive surrogate marker for trabecular bone volume and microarchitecture.MethodsBaseline vertebral fracture severity was determined by semiquantitative assessment of spine radiographs from 190 postmenopausal women with osteoporosis. Bone-structure indices were obtained by 2D histomorphometry and 3D microcomputed tomography (CT) analyses. Significance of differences was determined after adjusting for age, height, and lumbar spine bone mineral density.ResultsThere were significant (Pu2009<u20090.05) trends in decreasing bone volume, trabecular number, and connectivity, and increasing trabecular separation with greater vertebral fracture severity. Histomorphometric bone volume was 25 and 36% lower (Pu2009<u20090.05) in women with moderate and severe fractures than in women with no fractures, respectively. Compared with women without fractures, women with mild, moderate, and severe fractures had lower (Pu2009<u20090.05) microCT bone volume (23, 30, and 51%, respectively).ConclusionsMicroarchitectural deterioration was progressively worse in women with increasing severity of vertebral fractures. We conclude that assessment of vertebral fracture severity is an important clinical tool to evaluate the severity of postmenopausal osteoporosis.

Bisphosphonates alter trabecular bone collagen cross-linking and isomerization in beagle dog vertebra

SummaryChanges in organic matrix may contribute to the anti-fracture efficacy of anti-remodeling agents. Following one year of treatment in beagle dogs, bisphosphonates alter the organic matrix of vertebral trabecular bone, while raloxifene had no effect. These results show that pharmacological suppression of turnover alters the organic matrix component of bone.IntroductionThe collagen matrix contributes significantly to a bone’s fracture resistance yet the effects of anti-remodeling agents on collagen properties are unclear. The goal of this study was to assess changes in collagen cross-linking and isomerization following anti-remodeling treatment.MethodsSkeletally mature female beagles were treated for one year with oral doses of vehicle (VEH), risedronate (RIS; 3 doses), alendronate (ALN; 3 doses), or raloxifene (RAL; 2 doses). The middle dose of RIS and ALN and the lower dose of RAL approximate doses used for treatment of post menopausal osteoporosis. Vertebral trabecular bone matrix was assessed for collagen isomerization (ratio of α/β C-telopeptide [CTX]), enzymatic (pyridinoline [PYD] and deoxypyridinoline [DPD]), and non-enzymatic (pentosidine [PEN]) cross-links.ResultsAll doses of both RIS and ALN increased PEN (+34–58%) and the ratio of PYD/DPD (+14–26%), and decreased the ratio of α/β CTX (−29–56%) compared to VEH. RAL did not alter any collagen parameters. Bone turnover rate was significantly correlated to PEN (Ru2009=u2009−0.664), α/β CTX (Ru2009=u20090.586), and PYD/DPD (Ru2009=u2009−0.470).ConclusionsBisphosphonate treatment significantly alters properties of bone collagen suggesting a contribution of the organic matrix to the anti-fracture efficacy of this drug class.

Reconstructing the skeleton with intermittent parathyroid hormone

The aim of treating osteoporosis is to restore bone strength by increasing its mass and reconstructing its architecture. Antiresorptive drugs reduce bone remodeling, allowing more complete secondary mineralization of the existing bone; the mass, macro- and microarchitecture of the bone remains unchanged. Anabolic agents have the potential to achieve this goal. Parathyroid hormone (PTH) is famous for its catabolic actions. Its anabolic effects, known by a select few over 70 years ago, are finally being appreciated. There is widely reproduced and compelling evidence in a range of species made osteoporotic by gonadectomy that intermittent PTH administration restores bone strength by stimulating new bone formation on the periosteal (outer) and endosteal (inner) bone surfaces, enlarging bone diameter, thickening the cortices and existing trabeculae, and perhaps increasing trabecular numbers and their connectivity.

Risedronate dosing before breakfast compared with dosing later in the day in women with postmenopausal osteoporosis

SummaryTwo studies in postmenopausal women with osteoporosis provide information about the efficacy and safety of dosing oral risedronate 5xa0mg daily at a time other than before breakfast (i.e., 2xa0h before and 2xa0h after any food and drink other than plain water). A significant increase in lumbar spine BMD was observed for both treatment regimens in the two studies. However, smaller increases in lumbar spine BMD were observed with flexible dosing versus before-breakfast dosing. Geographic region, compliance, and consistency of dosing time appear to affect the amount of increase in BMD observed with flexible dosing.IntroductionTwo studies in postmenopausal women with osteoporosis provide additional information about the efficacy and safety of dosing oral risedronate 5xa0mg daily at a time other than before breakfast (i.e., 2xa0h before and 2xa0h after any food and drink other than plain water).MethodsOne study, flexible dosing, was a 6-month North American study in 730 patients randomized to before-breakfast dosing or flexible dosing later in the day. A second study, IMPACT, was a large (Nu2009=u20092382), 1-year multinational study in patients that chose their dosing regimen (before breakfast or later in the day). These studies were used to examine the bone mineral density (BMD) response with different dosing regimens.ResultsA significant increase in lumbar spine BMD was observed for both treatment regimens in the two studies. However, in both studies, the flexible dosing group had a smaller increase from baseline compared to the before-breakfast regimen (ratio of flexible dosing to before breakfast: flexible dosing study, 0.52; IMPACT study, 0.75). In addition, a relationship between geographic region and BMD response was observed with flexible dosing in both studies. Patients in the flexible dosing group who had greater dosing compliance (based on the number of times the bottle was opened) and consistency of dosing time (bottle opened within a 1.5-h window) had a greater increase in lumbar spine BMD.ConclusionResults of these two studies demonstrate that overall flexible dosing of risedronate leads to smaller BMD gains compared to before-breakfast dosing. This result may be due to poorer adherence to the flexible dosing instructions that may be more pronounced in patients in certain geographic regions. If patients cannot abide by before-breakfast dosing and flexible dosing is an approved option, one can expect suboptimal BMD results with flexible dosing.