Bruce H. Mitlak

Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women.

BACKGROUND Long-term estrogen therapy can reduce the risk of osteoporotic fracture and cardiovascular disease in postmenopausal women. At present, however, these beneficial effects are not separable from undesirable stimulation of breast and endometrial tissues. METHODS We studied the effect of raloxifene, a nonsteroidal benzothiophene, on bone mineral density, serum lipid concentrations, and endometrial thickness in 601 postmenopausal women. The women were randomly assigned to receive 30, 60, or 150 mg of raloxifene or placebo daily for 24 months. RESULTS The women receiving each dose of raloxifene had significant increases from base-line values in bone mineral density of the lumbar spine, hip, and total body, whereas those receiving placebo had decreases in bone mineral density. For example, at 24 months, the mean (+/-SE) difference in the change in bone mineral density between the women receiving 60 mg of raloxifene per day and those receiving placebo was 2.4+/-0.4 percent for the lumbar spine, 2.4+/-0.4 percent for the total hip, and 2.0+/-0.4 percent for the total body (P<0.001 for all comparisons). Serum concentrations of total cholesterol and low-density lipoprotein cholesterol decreased in all the raloxifene groups, whereas serum concentrations of high-density lipoprotein cholesterol and triglycerides did not change. Endometrial thickness was similar in the raloxifene and placebo groups at all times during the study. The proportion of women receiving raloxifene who reported hot flashes or vaginal bleeding was not different from that of the women receiving placebo. CONCLUSIONS Daily therapy with raloxifene increases bone mineral density, lowers serum concentrations of total and low-density lipoprotein cholesterol, and does not stimulate the endometrium.

Recombinant Human Parathyroid Hormone (1-34) (Teriparatide) Improves Both Cortical and Cancellous Bone Structure

Histomorphometry and μCT of 51 paired iliac crest biopsy specimens from women treated with teriparatide revealed significant increases in cancellous bone volume, cancellous bone connectivity density, cancellous bone plate‐like structure, and cortical thickness, and a reduction in marrow star volume.

Relationships Between Bone Mineral Density and Incident Vertebral Fracture Risk with Raloxifene Therapy

Although low absolute values of bone mineral density (BMD) predict increased fracture risk in osteoporosis, it is not certain how well increases in BMD with antiresorptive therapy predict observed reductions in fracture risk. This work examines the relationships between changes in BMD after 1 year or 3 years of raloxifene or placebo therapy and the risk for new vertebral fractures at 3 years. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis were randomized to placebo or raloxifene 60 mg/day or 120 mg/day. Relationships between baseline BMD and changes in BMD from baseline with the risk of new vertebral fractures were analyzed in this cohort using logistic regression models with the raloxifene doses pooled. As has been observed in other populations, women with the lowest baseline lumbar spine or femoral neck BMD in the MORE cohort had the greatest risk for vertebral fractures. Furthermore, for any percentage change, either increase or decrease in femoral neck or lumbar spine BMD at 1 year or 3 years, raloxifene‐treated patients had a statistically significantly lower vertebral fracture risk compared with placebo‐treated patients. The decrease in fracture risk with raloxifene was similar across the range of percentage change in femoral neck BMD observed at 3 years; patients receiving raloxifene had a 36% lower risk of vertebral fracture compared with those receiving placebo. At any percentage change in femoral neck and lumbar spine BMD observed at 1 year, raloxifene treatment decreased the risks of new vertebral fractures at 3 years by 38% and 41%, respectively. The logistic regression model showed that the percentage changes in BMD with raloxifene treatment accounted for 4% of the observed vertebral fracture risk reduction, and the other 96% of the risk reduction remains unexplained. The present data show that the measured BMD changes observed with raloxifene therapy are poor predictors of vertebral fracture risk reduction with raloxifene therapy.

Teriparatide for acceleration of fracture repair in humans: A prospective, randomized, double‐blind study of 102 postmenopausal women with distal radial fractures

Animal experiments show a dramatic improvement in skeletal repair by teriparatide. We tested the hypothesis that recombinant teriparatide, at the 20 µg dose normally used for osteoporosis treatment or higher, would accelerate fracture repair in humans. Postmenopausal women (45 to 85 years of age) who had sustained a dorsally angulated distal radial fracture in need of closed reduction but no surgery were randomly assigned to 8 weeks of once‐daily injections of placebo (n = 34) or teriparatide 20 µg (n = 34) or teriparatide 40 µg (n = 34) within 10 days of fracture. Hypotheses were tested sequentially, beginning with the teriparatide 40 µg versus placebo comparison, using a gatekeeping strategy. The estimated median time from fracture to first radiographic evidence of complete cortical bridging in three of four cortices was 9.1, 7.4, and 8.8 weeks for placebo and teriparatide 20 µg and 40 µg, respectively (overall p = .015). There was no significant difference between the teriparatide 40 µg versus placebo groups (p = .523). In post hoc analyses, there was no significant difference between teriparatide 40 µg versus 20 µg (p = .053); however, the time to healing was shorter in teriparatide 20 µg than placebo (p = .006). The primary hypothesis that teriparatide 40 µg would shorten the time to cortical bridging was not supported. The shortened time to healing for teriparatide 20 µg compared with placebo still may suggest that fracture repair can be accelerated by teriparatide, but this result should be interpreted with caution and warrants further study.

Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone (PTH 1-34).

BACKGROUND Recombinant human parathyroid hormone (PTH [1-34]; teriparatide) is a new treatment for postmenopausal osteoporosis that can be systemically administered for the primary purpose of increasing bone formation. Because several studies have described the enhancement of fracture-healing and osteointegration in animals after use of PTH, we sought to critically analyze this skeletal effect. METHODS Two hundred and seventy male Sprague-Dawley rats underwent standard, closed femoral fractures and were divided into three groups that were administered daily subcutaneous injections of 5 or 30 mug/kg of PTH (1-34) or vehicle (control). The dosing was administered for up to thirty-five days. Groups were further divided into three subgroups and were killed on day 21, 35, or 84 after the fracture. The bones were subjected to mechanical torsion testing, histomorphometric analysis, or microquantitative computed tomography. RESULTS By day 21, calluses from the group treated with 30 mug of PTH showed significant increases over the controls with respect to torsional strength, stiffness, bone mineral content, bone mineral density, and cartilage volume. By day 35, both groups treated with PTH showed significant increases in bone mineral content and density and total osseous tissue volume, and they demonstrated significant decreases in void space and cartilage volume (p < 0.05). Torsional strength was significantly increased at this time-point in the group treated with 30 mug of PTH (p < 0.05). While dosing was discontinued on day 35, analyses performed after eighty-four days in the group treated with 30 mug of PTH showed sustained increases over the controls with respect to torsional strength and bone mineral density. No change was noted in osteoclast density at the time-points measured, suggesting that treatment with PTH enhanced bone formation but did not induce bone resorption. CONCLUSIONS These data show that daily systemic administration of PTH (1-34) enhances fracture-healing by increasing bone mineral content and density and strength, and it produces a sustained anabolic effect throughout the remodeling phase of fracture-healing.

Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data

Summary Background Tamoxifen and raloxifene reduce the risk of breast cancer in women at elevated risk of disease, but the duration of the effect is unknown. We assessed the effectiveness of selective oestrogen receptor modulators (SERMs) on breast cancer incidence. Methods We did a meta-analysis with individual participant data from nine prevention trials comparing four selective oestrogen receptor modulators (SERMs; tamoxifen, raloxifene, arzoxifene, and lasofoxifene) with placebo, or in one study with tamoxifen. Our primary endpoint was incidence of all breast cancer (including ductal carcinoma in situ) during a 10 year follow-up period. Analysis was by intention to treat. Results We analysed data for 83 399 women with 306 617 women-years of follow-up. Median follow-up was 65 months (IQR 54–93). Overall, we noted a 38% reduction (hazard ratio [HR] 0·62, 95% CI 0·56–0·69) in breast cancer incidence, and 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. The reduction was larger in the first 5 years of follow-up than in years 5–10 (42%, HR 0·58, 0·51–0·66; p<0·0001 vs 25%, 0·75, 0·61–0·93; p=0·007), but we noted no heterogeneity between time periods. Thromboembolic events were significantly increased with all SERMs (odds ratio 1·73, 95% CI 1·47–2·05; p<0·0001). We recorded a significant reduction of 34% in vertebral fractures (0·66, 0·59–0·73), but only a small effect for non-vertebral fractures (0·93, 0·87–0·99). Interpretation For all SERMs, incidence of invasive oestrogen (ER)-positive breast cancer was reduced both during treatment and for at least 5 years after completion. Similar to other preventive interventions, careful consideration of risks and benefits is needed to identify women who are most likely to benefit from these drugs. Funding Cancer Research UK.

Six and Twelve Month Changes in Bone Turnover are Related to Reduction in Vertebral Fracture Risk During 3 Years of Raloxifene Treatment in Postmenopausal Osteoporosis

Abstract: We studied the relationship between change in bone turnover and vertebral fracture risk during raloxifene therapy using 3-year data from the MORE trial, where 2622 of the 7705 randomized women had measurement of bone markers at baseline and after 6 and 12 months participation. Change in bone turnover was significantely related to future risk of vertebral fracture, also after adjusting for baseline vertebral fracture status and BMD. Thus, for a decrease of 9.3 mg/l in serum osteocalcin after 1 year’s raloxifene therapy, the odds ratio (OR) for a new vertebral fracture during 3 years was 0.69 (0.54–0.88), p= 0.003. Similarly, for a decrease of 5.91 mg/l in serum bone alkaline phosphatase, OR was 0.75 (0.62–0.92), p= 0.005. The change in BMD over 12 and 24 months was not related to fracture risk in any of the analyses. The strongest predictor for vertebral fracture was prevalent vertebral fracture – even during therapy. The predictive value of baseline BMD was in the same order of magnitude as bone turnover change during raloxifene treatment. In conclusion, the change in bone turnover is related to fracture risk during raloxifene therapy. In contrast the change in BMD is not related to fracture risk. The strongest predictor for vertebral fracture is prevalent vertebral fracture.

Effects of teriparatide and alendronate on vertebral strength as assessed by finite element modeling of QCT scans in women with osteoporosis.

FE modeling was used to estimate the biomechanical effects of teriparatide and alendronate on lumbar vertebrae. Both treatments enhanced predicted vertebral strength by increasing average density. This effect was more pronounced for teriparatide, which further increased predicted vertebral strength by altering the distribution of density within the vertebra, preferentially increasing the strength of the trabecular compartment.

The Skeletal Response to Teriparatide Is Largely Independent of Age, Initial Bone Mineral Density, and Prevalent Vertebral Fractures in Postmenopausal Women With Osteoporosis†

In a recent study of women with postmenopausal osteoporosis, treatment with teriparatide for a median of 19 months increased bone mineral density and decreased the risk of vertebral and nonvertebral fractures. Using the same cohort, the current study evaluated the relationship between these therapeutic effects and the patients baseline age, vertebral bone mineral density, and prevalent vertebral fractures. In women over 65 years of age, treatment resulted in a greater increase in vertebral bone mineral density than in younger women (treatment‐by‐age interaction, p = 0.037), but baseline age had no effect on the relative risk reduction for vertebral fractures (treatment‐by‐age interaction, p = 0.558). In women receiving placebo (with calcium and vitamin D), there was an inverse relationship between baseline vertebral bone mineral density and vertebral fracture risk. When compared across bone mineral density tertiles, the effects of teriparatide on the relative risk for developing new vertebral fractures and increase in vertebral bone mineral density did not differ significantly (p = 0.817 and p = 0.615, respectively). Teriparatide treatment significantly decreased vertebral fracture risk in patients with a vertebral bone mineral density T score of less than −3.3 or a score between −2.1 and −3.3 (p < 0.001 and p = 0.027, respectively) and showed a trend toward reduced fracture risk in the group with a T score greater than −2.1 (p = 0.115). Placebo‐treated women with two or more prevalent vertebral fractures had a significantly greater risk of developing new vertebral fractures than women with zero or one prevalent vertebral fracture (p < 0.001). When compared within prevalent vertebral fracture subgroups, the effects of teriparatide on the relative risk for developing new vertebral fractures were similar. The results of this study indicate that teriparatide offers clinical benefit to patients across a broad range of age and disease severity.

Frailty and sarcopenia: definitions and outcome parameters

An operational definition of musculoskeletal decline in older people is needed to allow development of interventions for prevention or treatment, as was developed for the treatment of osteoporosis. Frailty and sarcopenia are linked, but distinct, correlates of musculoskeletal aging that have many causes, including age-related changes in body composition, inflammation, and hormonal imbalance. With the emergence of a number of exciting candidate therapies to retard the loss of muscle mass with aging, the derivation of a consensual definition of sarcopenia and physical frailty becomes an urgent priority. Although several consensual definitions have been proposed, these require clinical validation. An operational definition, which might provide a threshold for treatment/trial inclusion, should incorporate a loss of muscle mass as well as evidence of a decrease in muscle strength and/or physical activity. Evidence is required for a link between improvements in the measures of muscle strength and/or physical activity and clinical outcomes to allow development of interventions to improve clinical outcomes in frail older patients.