Silvano Adami

Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis

BACKGROUND Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis. METHODS We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures. RESULTS As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab. CONCLUSIONS Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)

Alendronate for the treatment of osteoporosis in men

BACKGROUND Despite its association with disability, death, and increased medical costs, osteoporosis in men has been relatively neglected as a subject of study. There have been no large, controlled trials of treatment in men. METHODS In a two-year double-blind trial, we studied the effect of 10 mg of alendronate or placebo, given daily, on bone mineral density in 241 men (age, 31 to 87 years; mean, 63) with osteoporosis. Approximately one third had low serum free testosterone concentrations at base line; the rest had normal concentrations. Men with other secondary causes of osteoporosis were excluded. All the men received calcium and vitamin D supplements. The main outcome measures were the percent changes in lumbar-spine, hip, and total-body bone mineral density. RESULTS The men who received alendronate had a mean (+/-SE) increase in bone mineral density of 7.1+/-0.3 percent at the lumbar spine, 2.5+/-0.4 percent at the femoral neck, and 2.0+/-0.2 percent for the total body (P<0.001 for all comparisons with base line). In contrast, men who received placebo had an increase in lumbar-spine bone mineral density of 1.8+/-0.5 percent (P<0.001 for the comparison with base line) and no significant changes in femoral-neck or total-body bone mineral density. The increase in bone mineral density in the alendronate group was greater than that in the placebo group at all measurement sites (P<0.001). The incidence of vertebral fractures was lower in the alendronate group than in the placebo group (0.8 percent vs. 7.1 percent, P=0.02). Men in the placebo group had a 2.4-mm decrease in height, as compared with a decrease of 0.6 mm in the alendronate group (P=0.02). Alendronate was generally well tolerated. CONCLUSIONS In men with osteoporosis, alendronate significantly increases spine, hip, and total-body bone mineral density and helps prevent vertebral fractures and decreases in height.

Efficacy and Safety of Daily Risedronate in the Treatment of Corticosteroid-Induced Osteoporosis in Men and Women: A Randomized Trial*

Long‐term use of high‐dose corticosteroids often results in bone loss, which may lead to osteoporosis‐related fractures. This was a multicenter, double‐blind study in which 290 ambulatory men and women receiving high‐dose oral corticosteroid therapy (prednisone ≥ 7.5 mg/day or equivalent) for 6 or more months were randomized to receive placebo, risedronate 2.5 mg/day, or risedronate 5 mg/day for 12 months. All patients received calcium 1 g and vitamin D 400 IU daily. The primary endpoint was lumbar spine bone mineral density (BMD) at month 12. Additional measurements included BMD at the femoral neck and trochanter and the incidence of vertebral fractures. Overall, there were statistically significant treatment effects on BMD at 12 months at the lumbar spine (p < 0.001), femoral neck (p = 0.004), and trochanter (p = 0.010). Risedronate 5 mg increased BMD at 12 months by a mean (SEM) of 2.9% (0.49%) at the lumbar spine, 1.8% (0.46%) at the femoral neck, and 2.4% (0.54%) at the trochanter, whereas BMD was maintained only in the control group. Although not powered to show fracture efficacy, we observed a reduction in the incidence of vertebral fractures of 70% in the combined risedronate treatment groups, relative to placebo (p = 0.042). Risedronate was well tolerated, had a good safety profile, and was not associated with gastrointestinal adverse events. We conclude that risedronate increases BMD and potentially reduces the incidence of vertebral fractures in patients with corticosteroid‐induced osteoporosis.

Bone loss in response to long-term glucocorticoid therapy

A number of studies have shown that an excess of glucocorticoids induces osteoporosis, but the mechanism(s) and the time course of the reduction of bone mass remain uncertain. In order to clarify this issue we carried out a longitudinal clinical and histomorphometric study of patients requiring long-term glucocorticoid treatment. In 23 patients (9 men, 10 post- and 4 premenopausal women) biochemical and bone histomorphometric investigations were carried out before and during treatment with 10-25 mg/day of prednisone. Histomorphometric analysis of bone biopsies of the iliac crest showed that the decrease of TBV (up to -27%, P less than 0.001) occurs predominantly within the first 5-7 months of treatment; during the subsequent stages, which include observations after 12 months of treatment, only minor changes were observed. Therefore trabecular bone loss can be satisfactorily described by a negative exponential function. None of the other histomorphometric parameters (osteoid surfaces, resorption surfaces, etc.) showed significant changes. However, the histological features of the bone biopsies during steroid therapy, showing a virtual lack of osteoblastic activity, ruled out an increase of bone resorption. Moreover, the dynamic study of the bone formation by double tetracycline labelling showed, in a small subgroup of patients, a decrease of the apposition rates (from 0.763 +/- 0.053 to 0.305 +/- 0.074 microns/day (mean +/- SE) after treatment). No significant changes, at any time during steroid treatment, were observed in serum alkaline phosphatase, 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, 1,25-dihydroxyvitamin D, parathyroid hormone or urinary calcium excretion. Serum calcium increased significantly within the first 1-2 months of therapy and then it returned to baseline. Urinary hydroxyproline excretion decreased significantly within the first 1-2 months and continued to fall throughout the treatment. Thus, both biochemical and histological findings suggest that long-term glucocorticoid therapy causes a reduction of bone turnover, that the bone loss occurs predominantly within the first 6 months of treatment and that patients with lower bone mass have a lower rate of bone loss.

Adverse effects of bisphosphonates. A comparative review.

SummaryThe bisphosphonates comprise a new class of drugs, and are increasingly being used to treat bone diseases characterised by increased osteoclastic bone resorption. These compounds are generally well tolerated, but toxicity may vary considerably from one compound to another.Dosages of etidronic acid above 800 mg/day impair the normal skeletal mineralisation and this may be associated with the appearance of fractures, but at the doses used for the treatment of osteoporosis, none of the bisphosphonates induce clinical or histological signs of impaired mineralisation.The skeletal half-life of bisphosphonates is of the order of several years, but this appears to be of little clinical consequence since the pharmacological effect is of relatively short duration. The mechanical properties of the skeleton of animals treated over long periods with high doses of various bisphosphonates have been shown to be perfectly preserved. However, in growing individuals, excess inhibition of bone remodelling might induce osteopetrotic-like alterations.When high doses of amino-bisphosphonates are given to patients who have never received bisphosphonate therapy, the patients may experience fevers up to 39°C for 1 to 3 days, associated with transient haematological changes resembling a typical acute-phase response.Rapid intravenous injection of bisphosphonates at doses greater than 200 to 300mg may cause severe renal failure; this can be prevented by slowing the rate of infusion (<200 mg/h). Administration of high doses of bisphosphonates to patients with high bone turnover may induce a rapid and transient drop in serum calcium which is seldom symptomatic.The gastrointestinal absorption of bisphosphonates is low, and they must be taken without food. Oral amino derivatives may induce dose-related serious gastrointestinal lesions, with the sporadic appearance of erosive oesophagitis.Amino-bisphosphonate administration has been also associated with the sporadic occurrence of uveitis, scleritis and phlebitis and, in single cases, with irritative reactions at the skin, peritoneum and pericardium.

Bisphosphonate therapy of reflex sympathetic dystrophy syndrome

OBJECTIVE The reflex sympathetic dystrophy syndrome (RSDS) is a painful limb disorder, for which a consistently effective treatment has not yet been identified. The disease is associated with increased bone resorption and patchy osteoporosis, which might benefit from treatment with bisphosphonates, powerful inhibitors of bone resorption. METHODS Twenty patients with RSDS of foot and hand, were randomly assigned to blind administration of either alendronate intravenously (Istituto Gentili, Pisa, Italy) 7.5 mg dissolved in 250 ml saline solution or placebo saline infusions daily for three days. Two weeks later all patients had an identical treatment course with open labelled alendronate (7.5 mg/day for three days), independent from the results of the first blind treatment. RESULTS In the patients treated with blind alendronate the diminution in spontaneous pain, tenderness, and swelling (circumference of the affected limb) and the improvement in motion were significantly different from baseline (p<0.001), from those observed within the first two weeks in the control group (p<0.01), and from week 2 to week 4 (p<0.01). In the patients given blind placebo infusions no relevant symptomatic changes were observed after the first two weeks of follow up, but they responded to the open alendronate therapy given afterwards. In 12 patients with RSDS of the hand the ultradistal bone mineral content (BMC) of the affected arm was considerably lower than that of the controlateral arm (mean (SD)) (426(82) mg/cm versus 688(49)). Six weeks after the beginning of the trial BMC rose by 77(12) mg/cm (p<0.001) in the affected arm, but it did not change in the controlateral. CONCLUSIONS These results indicate that bisphosphonates should be considered for the treatment of RSDS, producing consistent and rapid remission of the disease.

Intravenous neridronate in children with osteogenesis imperfecta: a randomized controlled study.

In a randomized controlled study, we investigated the effect of treatment with intravenous neridronate in prepubertal children with OI. Our study suggests that quarterly intravenous infusions of the bisphosphonate significantly raise the rate of increase in BMD at both the spine and hip, the projected area of the lumbar vertebrae, and height. These results are associated with a significant decrease in the risk of clinical fractures.

Effects of Oral Alendronate in Elderly Patients with Osteoporosis and Mild Primary Hyperparathyroidism

In a large proportion of the patients with primary hyperparathyroidism (PHPT), a variable degree of osteopenia is the only relevant manifestation of the disease. Low bone mineral density (BMD) in patients with PHPT is an indication for surgical intervention because successful parathyroidectomy results in a dramatic increase in BMD. However, low BMD values are almost an invariable finding in elderly women with PHPT, who are often either unwilling or considered unfit for surgery. Bisphosphonates are capable of suppressing parathyroid hormone (PTH)‐mediated bone resorption and are useful for the prevention and treatment of postmenopausal osteoporosis. In this pilot‐controlled study, we investigated the effects of oral treatment with alendronate on BMD and biochemical markers of calcium and bone metabolism in elderly women presenting osteoporosis and mild PHPT. Twenty‐six elderly patients aged 67–81 years were randomized for treatment with either oral 10 mg alendronate on alternate‐day treatment or no treatment for 2 years. In the control untreated patients a slight significant decrease was observed for total body and femoral neck BMD, without significant changes in biochemical markers of calcium and bone metabolism during the 2 years of observation. Urine deoxypyridinoline (Dpyr) excretion significantly fell within the first month of treatment with alendronate, while serum markers of bone formation alkaline phosphatase and osteocalcin fell more gradually and the decrease became significant only after 3 months of treatment; thereafter all bone turnover markers remained consistently suppressed during alendronate treatment. After 2 years in this group we observed statistically significant increases in BMD at lumbar spine, total hip, and total body (+8.6 ± 3.0%, +4.8 ± 3.9%, and +1.2 ± 1.4% changes vs. baseline mean ± SD) versus both baseline and control patients. Serum calcium, serum phosphate, and urinary calcium excretion significantly decreased during the first 3‐6 months but rose back to the baseline values afterward. Increase in serum PTH level was statistically significant during the first year of treatment. These preliminary results may make alendronate a candidate as a supportive therapy in patients with mild PHPT who are unwilling or are unsuitable for surgery, and for whom osteoporosis is a reason of concern.

Impact of Prevalent Fractures on Quality of Life: Baseline Results From the Global Longitudinal Study of Osteoporosis in Women

OBJECTIVE To examine several dimensions of health-related quality of life (HRQL) in postmenopausal women who report previous fractures, and to provide perspective by comparing these findings with those in other chronic conditions (diabetes, arthritis, lung disease). PATIENTS AND METHODS Fractures are a major cause of morbidity among older women. Few studies have examined HRQL in women who have had prior fractures and the effect of prior fracture location on HRQL. In this observational study of 57,141 postmenopausal women aged 55 years and older (enrollment from December 2007 to March 2009) from 17 study sites in 10 countries, HRQL was measured using the European Quality of Life 5 Dimensions Index (EQ-5D) and the health status, physical function, and vitality questions of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). RESULTS Reductions in EQ-5D health-utility scores and SF-36-measured health status, physical function, and vitality were seen in association with 9 of 10 fracture locations. Spine, hip, and upper leg fractures resulted in the greatest reductions in quality of life (EQ-5D scores, 0.62, 0.64, and 0.61, respectively, vs 0.79 without prior fracture). Women with fractures at any of these 3 locations, as well as women with a history of multiple fractures (EQ-5D scores, 0.74 for 1 prior fracture, 0.68 for 2, and 0.58 for >/=3), had reductions in HRQL that were similar to or worse than those in women with other chronic diseases (0.67 for diabetes, 0.69 for arthritis, and 0.71 for lung disease). CONCLUSION Previous fractures at a variety of bone locations, particularly spine, hip, and upper leg, or involving more than 1 location are associated with significant reductions in quality of life.

Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and nonvertebral fractures

Dual‐energy X‐ray absorptiometric bone mineral density (DXA BMD) is a strong predictor of fracture risk in untreated patients. However, previous patient‐level studies suggest that BMD changes explain little of the fracture risk reduction observed with osteoporosis treatment. We investigated the relevance of DXA BMD changes as a predictor for fracture risk reduction using data from the FREEDOM trial, which randomly assigned placebo or denosumab 60 mg every 6 months to 7808 women aged 60 to 90 years with a spine or total hip BMD T‐score < −2.5 and not < −4.0. We took a standard approach to estimate the percent of treatment effect explained using percent changes in BMD at a single visit (months 12, 24, or 36). We also applied a novel approach using estimated percent changes in BMD from baseline at the time of fracture occurrence (time‐dependent models). Denosumab significantly increased total hip BMD by 3.2%, 4.4%, and 5.0% at 12, 24, and 36 months, respectively. Denosumab decreased the risk of new vertebral fractures by 68% (p < 0.0001) and nonvertebral fracture by 20% (p = 0.01) over 36 months. Regardless of the method used, the change in total hip BMD explained a considerable proportion of the effect of denosumab in reducing new or worsening vertebral fracture risk (35% [95% confidence interval (CI): 20%–61%] and 51% [95% CI: 39%–66%] accounted for by percent change at month 36 and change in time‐dependent BMD, respectively) and explained a considerable amount of the reduction in nonvertebral fracture risk (87% [95% CI: 35% – >100%] and 72% [95% CI: 24% – >100%], respectively). Previous patient‐level studies may have underestimated the strength of the relationship between BMD change and the effect of treatment on fracture risk or this relationship may be unique to denosumab.