David J. Hosking

PREVENTION OF BONE LOSS WITH ALENDRONATE IN POSTMENOPAUSAL WOMEN UNDER 60 YEARS OF AGE

Background Estrogen-replacement therapy prevents osteoporosis in postmenopausal women by inhibiting bone resorption, but the balance between its long-term risks and benefits remains unclear. Whether other antiresorptive therapies can prevent osteoporosis in these women is also not clear. Methods We studied the effect of 2.5 mg or 5 mg of alendronate per day or placebo on bone mineral density in 1174 postmenopausal women under 60 years of age. An additional 435 women who were prepared to receive a combination of estrogen and progestin were randomly assigned to one of the above treatments or open-label estrogen–progestin. The main outcome measure was the change in bone mineral density of the lumbar spine, hip, distal forearm, and total body measured annually for two years by dual-energy x-ray absorptiometry. Results The women who received placebo lost bone mineral density at all measured sites, whereas the women treated with 5 mg of alendronate daily had a mean (±SE) increase in bone mineral density of 3.5±...

Effects of Risedronate Treatment on Bone Density and Vertebral Fracture in Patients on Corticosteroid Therapy

Abstract. Men and women (n = 518) receiving moderate-to-high doses of corticosteroids were enrolled in two studies with similar protocols and randomly assigned to receive either placebo or risedronate (2.5 or 5 mg) for 1 year. All patients received daily calcium supplementation (500–1000 mg), and most also received supplemental vitamin D (400 IU). The primary endpoint was the difference between the placebo and active groups in lumbar spine bone mineral density (BMD) at 1 year; changes in BMD at other sites, biochemical markers of bone turnover, and the incidence of vertebral fractures were also assessed. In the overall population, the mean (SE) lumbar spine BMD increased 1.9 ± 0.38% from baseline in the risedronate 5 mg group (P < 0.001) and decreased 1.0 ± 0.4% in the placebo group (P= 0.005). BMD at the femoral neck, trochanter, and distal radius increased or was maintained with risedronate 5 mg treatment, but decreased in the placebo group. Midshaft radius BMD did not change significantly in either treatment group. The difference in BMD between the risedronate 5 mg and placebo groups was significant at all skeletal sites (P < 0.05) except the midshaft radius at 1 year. The 2.5 mg dose also had a positive effect on BMD, although of a lesser magnitude than that seen with risedronate 5 mg. A significant reduction of 70% in vertebral fracture risk was observed in the risedronate 5 mg group compared with the placebo group (P= 0.01). Risedronate was efficacious in both men and women, irrespective of underlying disease and duration of corticosteroid therapy, and had a favorable safety profile, with a similar incidence of upper gastrointestinal adverse events in the placebo and active treatment groups. Daily treatment with risedronate 5 mg significantly increases BMD and decreases vertebral fracture risk in patients receiving moderate-to-high doses of corticosteroid therapy.

Low body mass index is an important risk factor for low bone mass and increased bone loss in early postmenopausal women

Thinness (low percentage of body fat, low body mass index [BMI], or low body weight) was evaluated as a risk factor for low bone mineral density (BMD) or increased bone loss in a randomized trial of alendronate for prevention of osteoporosis in recently postmenopausal women with normal bone mass (n = 1609). The 2‐year data from the placebo group were used (n = 417). Percentage of body fat, BMI, and body weight were correlated with baseline BMD (r = −0.13 to −0.43, p < 0.01) and 2‐year bone loss (r = −0.14 to −0.19, p < 0.01). Women in the lowest tertiles of percentage of body fat or BMI had up to 12% lower BMD at baseline and a more than 2‐fold higher 2‐year bone loss as compared with women in the highest tertiles (p ≤ 0.004). Women with a lower percentage of body fat or BMI had higher baseline levels of urine N‐telopeptide cross‐links (r = −0.24 to −0.31, p < 0.0001) and serum osteocalcin (r = −0.12 to −0.15, p < 0.01). To determine if the magnitude of treatment effect of alendronate was dependent on these risk factors, the group treated with 5 mg of alendronate was included (n = 403). There were no associations between fat mass parameters and response to alendronate treatment, which indicated that risk of low bone mass and increased bone loss caused by thinness could be compensated by alendronate treatment. In conclusion, thinness is an important risk factor for low bone mass and increased bone loss in postmenopausal women. Because the response to alendronate treatment is independent of fat mass parameters, prevention of postmenopausal osteoporosis can be equally achieved in thinner and heavier women.

Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience

Limited placebo-controlled data are available to assess the long-term fracture efficacy of bisphosphonates. In order to determine the effects of 5 years of risedronate treatment, we extended a 3-year, placebo-controlled vertebral fracture study in osteoporotic women for an additional 2 years; women who entered the extension study continued to receive 5 mg risedronate or placebo according to the original randomization, with maintenance of blinding. End points included vertebral and nonvertebral fracture assessments, bone mineral density measurements, and changes in biochemical markers of bone turnover. A total of 265 women (placebo, 130; 5 mg risedronate, 135) entered the study extension and 220 (83%) completed the additional 2 years. Fracture results observed in the study extension were consistent with those observed in the first 3 years. The risk of new vertebral fractures was significantly reduced with risedronate treatment in years 4 and 5 by 59% (95% confidence interval, 19 to 79%, P = 0.01) compared with a 49% reduction in the first 3 years. Rapid and significant decreases in markers of bone turnover observed in the first 3 years were similarly maintained in the next 2 years of treatment. Increases in spine and hip bone mineral density that occurred in the risedronate group during the first 3 years were maintained or increased with a further 2 years of treatment. The mean increase from baseline in lumbar spine BMD over 5 years was 9.3% (P < 0.001). This study demonstrates that the effects of risedronate over 3 years on vertebral fracture and BMD are maintained with a further 2 years of treatment.

Odanacatib in the treatment of postmenopausal women with low bone mineral density: Three-year continued therapy and resolution of effect

The selective cathepsin K inhibitor odanacatib (ODN) progressively increased bone mineral density (BMD) and decreased bone‐resorption markers during 2 years of treatment in postmenopausal women with low BMD. A 1‐year extension study further assessed ODN efficacy and safety and the effects of discontinuing therapy. In the base study, postmenopausal women with BMD T‐scores between −2.0 and −3.5 at the lumbar spine or femur received placebo or ODN 3, 10, 25, or 50 mg weekly. After 2 years, patients (n = 189) were rerandomized to ODN 50 mg weekly or placebo for an additional year. Endpoints included BMD at the lumbar spine (primary), total hip, and hip subregions; levels of bone turnover markers; and safety assessments. Continued treatment with 50 mg of ODN for 3 years produced significant increases from baseline and from year 2 in BMD at the spine (7.9% and 2.3%) and total hip (5.8% and 2.4%). Urine cross‐linked N‐telopeptide of type I collagen (NTx) remained suppressed at year 3 (−50.5%), but bone‐specific alkaline phosphatase (BSAP) was relatively unchanged from baseline. Treatment discontinuation resulted in bone loss at all sites, but BMD remained at or above baseline. After ODN discontinuation at month 24, bone turnover markers increased transiently above baseline, but this increase largely resolved by month 36. There were similar overall adverse‐event rates in both treatment groups. It is concluded that 3 years of ODN treatment resulted in progressive increases in BMD and was generally well tolerated. Bone‐resorption markers remained suppressed, whereas bone‐formation markers returned to near baseline. ODN effects were reversible: bone resorption increased transiently and BMD decreased following treatment discontinuation.

Oral alendronate induces progressive increases in bone mass of the spine, hip, and total body over 3 years in postmenopausal women with osteoporosis

To determine the effects of long-term daily oral alendronate sodium (ALN) on bone mass in postmenopausal women with osteoporosis, 19 centers enrolled 516 postmenopausal women aged 45-80 years with spine bone mineral density (BMD) at least 2.5 SD below the mean for young premenopausal women in a 3-year, double-blind, placebo-controlled study. Subjects were randomly allocated to one of four treatment groups: placebo; alendronate, 5 or 10 mg/day for 3 years; or alendronate, 20 mg/day for 2 years followed by 5 mg/day for the 3rd year. All patients received 500 mg/day of supplemental calcium to ensure adequate calcium intake. BMD was measured by dual-energy X-ray absorptiometry at several skeletal sites. Nonsignificant mean decreases in BMD of the spine, femoral neck, and trochanter of 0.6, 0.7, and 0.4%, respectively, occurred in the placebo group at 3 years. Relative to placebo-treated patients, spine BMD increased by 5.4%, 7.4%, and 8.4% in the 5, 10, and 20/5 mg ALN groups, respectively. Increases at the femoral neck were 3.5%, 5.5%, and 4.3%, and those at the trochanter were 5.1%, 7.2%, and 7.2%, respectively. Thus, efficacy of 10 and 20/5 mg ALN was similar, whereas the 5 mg dose was less effective. BMD continued to increase over the entire 3-year study duration in the ALN-treated groups and, compared with the other dosage groups, 10 mg ALN produced the largest gains in BMD during the 3rd year. Changes in biochemical markers of bone turnover and mineral homeostasis confirmed the effect of ALN to decrease bone turnover to a new steady-state level. The safety and tolerability of ALN were comparable with those of placebo. In summary, 10 mg daily oral ALN given for 3 years significantly and progressively increases bone mass and is a generally well-tolerated treatment for osteoporosis in postmenopausal women.

Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate: A randomized, placebo-controlled trial

PURPOSE The potent bisphosphonates offer great promise in the management of Pagets disease of bone, but are currently available only as parenteral preparations in most countries. There is a need for a well-tolerated, oral therapy. Furthermore, none of the currently available therapies have been rigorously demonstrated to heal the lytic bone lesions characteristic of this condition. Alendronate is a potent new oral aminobisphosphonate that has shown promising effects on Pagets disease in preliminary studies. METHODS We report a double-blind, randomized comparison of oral alendronate 40 mg/day and placebo over 6 months in 55 patients with Pagets disease. Efficacy was determined from measurements of biochemical indices of bone turnover (serum alkaline phosphatase and urine N-telopeptide) and blinded radiologic assessment of lytic bone lesions. RESULTS N-telopeptide excretion declined by 86% and serum alkaline phosphatase by 73% in patients receiving alendronate, but remained stable in patients receiving placebo (P < 0.001 between groups for both indices). Responses were similar whether or not patients had previously received bisphosphonate treatment. Alendronate treatment normalized alkaline phosphatase in 48% of patients. Forty-eight percent of alendronate-treated patients showed radiologic improvement in osteolysis whereas in the placebo group only 4% improved (P = 0.02 for between-groups comparison). No patient in either group showed worsening of osteolysis. Bone histomorphometry indicated that alendronate tended to normalize turnover indices. There was no evidence of abnormal mineralization in bone biopsies taken from 12 alendronate-treated subjects. The treatment was well tolerated. CONCLUSION Oral alendronate appears to be a safe and effective therapy for Pagets disease and results in healing of lytic bone lesions.

Vitamin D insufficiency increases bone turnover markers and enhances bone loss at the hip in patients with established vertebral osteoporosis

The aim of this study was to determine whether the presence of vitamin D insufficiency increases bone turnover and enhances bone loss by examining the relationship between bone turnover markers and Bone mineral density (BMD) in vitamin D insufficient and vitamin D sufficient patients, with established vertebral osteoporosis.

Long-Term Control of Bone Turnover in Paget's Disease With Zoledronic Acid and Risedronate

A single 5‐mg infusion of zoledronic acid restores biochemical markers of bone turnover into the reference range in the majority of patients with Pagets disease and maintains biochemical remission for at least 2 years. This effect is largely independent of pretreatment disease activity and prior bisphosphonate therapy.

Vitamin D status in renal transplant recipients

Vitamin D plays an important role in calcium homeostasis. Renal transplant recipients may be more susceptible to reduced levels because of decreased sun exposure and steroid therapy. This study aimed to determine vitamin D status after renal transplantation and its effect on parathyroid hormone (PTH) and bone mineral density (BMD). We measured serum 25‐hydroxyvitamin D levels (25‐OHD) in 244 renal transplant recipients, divided into two groups, 104 recently transplanted (less than 1 year) and 140 long‐term. Vitamin D status was defined according to NKF/KDOQI guidelines. Mean 25‐OHD levels were 33 ± 19 nmol/L and 42 ± 20 nmol/L, respectively, for the recent and long‐term transplant recipients. Vitamin D insufficiency was present in 29% and 43%, deficiency in 56% and 46% and severe deficiency in 12% and 5%, respectively. An inverse correlation was found between logPTH and 25‐OHD (r=−0.2, p= 0.019) in long‐term but not in recently transplanted patients. No correlation was found between 25‐OHD levels and BMD. Hypercalcaemia was present in 40% of the recently transplanted recipients and 25% of the long‐term. In conclusion 25‐OHD was low in virtually all of our renal transplant recipients and may aggravate secondary hyperparathyroidism, but its correction may be difficult in patients with hypercalcaemia.