Effect of intravenous pamidronate on bone mineral density in adults with cystic fibrosis. Intravenous zoledronate improves bone density in adults with cystic fibrosis (CF). Efficacy of pamidronate for osteoporosis in patients with cystic fibrosis following lung transplantation. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. Two-year clinical trial of oral alendronate versus intravenous pamidronate in children with osteogenesis imperfecta. Efficacy of alendronate in adults with cystic fibrosis with low bone density. Zoledronic acid to prevent bone loss in the first 6 months after renal transplantation. Therapy of steroid-induced bone loss in adult asthmatics with calcium, vitamin D, and a diphosphonate. Intravenous neridronate in adults with osteogenesis imperfecta.
Low bone mineral density (BMD) is prevalent in adults with cystic fibrosis. The aim of this study was to assess the effect of intravenous pamidronate on BMD in these subjects.
                Patients were invited to participate if they had a BMD Z score of -2 or less in the lumbar spine, proximal femur, or distal forearm. Patients were randomised to receive either 30 mg intravenous pamidronate every 3 months + 1 g calcium daily (pamidronate group) or 1 g calcium daily (control group). All pancreatic insufficient patients were prescribed oral vitamin D supplements.
                After 6 months of treatment the pamidronate group (n=13) showed a significant increase in absolute BMD compared with the control group (n=15) in the lumbar spine (mean difference 5.8% (CI 2.7% to 8.9%)) and total hip (mean difference 3.0% (CI 0.3% to 5.6%)). However, the pamidronate group showed a reduction in BMD compared with the control group in the distal forearm (mean difference -1.7% (CI -3.7% to 0.3%)). The use of pamidronate was associated with a high incidence of bone pain in non-corticosteroid treated individuals.
                Intravenous pamidronate increases axial BMD in adults with cystic fibrosis, but the high incidence of bone pain associated with this treatment might limit its use. Reduced bone mineral density (BMD) and increased rates of atraumatic fracture are observed in cystic fibrosis (CF) patients, causing increasing morbidity as this population ages. The study aimed to assess the safety, tolerability and effect on BMD of intravenous zoledronate in adults with CF and osteopaenia.
                Randomized, double-blind, placebo-controlled clinical trial.
                Adult CF outpatient clinics at two hospitals.
                Twenty-two non-transplanted CF patients aged > or = 18 years with a bone densitometry T-score of < -1.5 at one of three sites (lumbar spine, femoral neck, distal forearm) were studied. Participants were randomized to receive either 2 mg zoledronate i.v. (n = 10) or normal saline (placebo, n = 12) every 3 months for 2 years (8 infusions). All participants received calcium and vitamin D supplements twice daily.
                Percentage change in areal BMD from baseline.
                Lumbar spine BMD increased from baseline more with zoledronate than placebo at 6 months (5.35 +/- 0.76 vs. 1.19 +/- 1.20%, P = 0.012), 12 months (6.6 +/- 1.5 vs. 0.35 +/- 1.55%, P = 0.011) and 24 months (6.14 +/- 1.86 vs. 0.44 +/- 0.10, P = 0.021). Femoral neck BMD increased more after zoledronate than placebo at 6 months (3.2 +/- 1.6 vs.-1.43 +/- 0.43%, P = 0.019), 12 months (4.12 +/- 1.8 vs.-1.59 +/- 1.4%, P = 0.024) and 24 months (4.23 +/- 1.3 vs.-2.5 +/- 1.41%, P = 0.0028). Forearm BMD did not change. Zoledronate was associated with flu-like and musculoskeletal side effects, particularly after the first infusion. There were no fractures in either group.
                Intravenous zoledronate was significantly more effective than placebo for increasing BMD in adults with CF and osteopaenia, but side effects limited its tolerability. Lung transplantation with its attendant life-long immunosuppression contributes to bone loss and its sequelae, fractures and kyphosis, in patients with lung disease, many of whom already suffer from severe osteoporosis. Patients with cystic fibrosis (CF) are one of the most severely affected groups. We conducted a controlled, randomized, nonblinded trial of pamidronate (30 mg intravenously every 3 mo) with vitamin D (800 IU/d) and calcium (1 g/d) (n = 16) compared with vitamin D and calcium alone (n = 18, the control subjects) for 2 yr in 34 patients after lung transplant to improve bone mineral density (BMD). The treatment groups were similar in age, sex, baseline T-scores, renal function, hospitalization rates, immunosuppressant levels, change in lung function, and body mass index (BMI) over the study period. The patients treated with pamidronate gained 8.8 +/- 2.5% and 8.2 +/- 3.8% in spine and femur BMD after 2 yr in comparison to control subjects, who gained, on average (+/- SD), 2.6 +/- 3.2 and 0.3 +/- 2.2%, respectively (p </= 0.015 for both). Seven and six fractures occurred in the control and pamidronate groups, respectively (p > 0.2). Measures of bone resorption were highest immediately after lung transplant and improved with both pamidronate and time. Measures of bone formation were very poor after lung transplant, but recovered in the first post-lung transplant year irrespective of therapy. We conclude that pamidronate was more effective than control in improving bone mineral density after lung transplantation in patients with CF and appears to be one of the most promising agents studied to date for posttransplant osteoporosis. Osteolytic metastases often give rise to hypercalcemia, fracture, and bone pain, and occur commonly in patients with recurrent breast cancer. We assessed the bisphosphonate, clodronate, which has proven to be a useful treatment for hypercalcemia and may be a potent inhibitor of tumor-induced osteolysis, for its effect on reducing the osseous complications of metastatic breast cancer.
                We studied 173 patients with bone metastases due to breast cancer in a randomized, double-blind, placebo-controlled trial of oral clodronate 1,600 mg/d (85 patients) compared with an identical placebo (88 patients).
                The patients in each wing were comparable in their clinical, radiologic, and biochemical characteristics at trial entry. In patients who received clodronate, there was a significant reduction compared with placebo in the total number of hypercalcemic episodes (28 v 52; P < .01), in the number of terminal hypercalcemic episodes (seven v 17; P < .05), in the incidence of vertebral fractures (84 v 124 per 100 patient-years; P < .025), and in the rate of vertebral deformity (168 v 252 per 100 patient-years; P < .001). The combined rate of all morbid skeletal events was significantly reduced (218.6 v 304.8 per 100 patient-years; P < .001). Trends were seen in favor of clodronate for nonvertebral fracture rates and radiotherapy requirements for bone pain (particularly spinal pain). No significant survival differences and no significant differences in side effects were observed between the two groups.
                These findings indicate that oral clodronate has a beneficial effect on the skeletal morbidity associated with breast cancer and should be considered as antiosteolytic therapy in affected patients. It deserves further investigation as an adjuvant therapy in operable breast cancer and in patients with nonosseous recurrence who are at high risk for bone metastases. A 2-year prospective, partially randomized open-label trial comparing oral alendronate with intravenous pamidronate therapy in children with OI showed equivalence in increasing total body BMD, spine BMD, and linear growth, and decreasing bone turnover and fracture incidence. Children with mild OI had greater responses than severe OI in BMD and growth.
                Bisphosphonate therapies increase BMD and may reduce fractures in children with osteogenesis imperfecta (OI). A study directly comparing oral with intravenous bisphosphonate has not been published. This clinical trial compares oral alendronate with intravenous pamidronate in children with OI using an open-label, prospective, 2-year, randomized design.
                Children over the age of 3 years were stratified by bone age, pubertal stage, and type of OI and then randomized to receive oral alendronate 1 mg/kg/day in tablet form or intravenous pamidronate, 3 mg/kg/4 months. One child was assigned to pamidronate. One child randomized to intravenous pamidronate changed to oral alendronate. Eighteen children completed 12 months of therapy: nine on oral alendronate and nine on intravenous pamidronate. Primary outcome efficacy was increase in BMD. Secondary outcomes included changes in bone turnover biomarkers, fracture incidence, and growth.
                Total body and lumbar spine BMD increased, turnover markers decreased, and linear growth increased equivalently with oral and intravenous therapy. Fracture incidence showed a trend to decrease in both groups, with a significant decrease in fracture rates when the oral and intravenous groups were pooled. There were greater responses in BMD and growth in children with milder OI (type I) than those with more severe disease (types III and IV), but there were no significant effects of age or pubertal stage.
                Oral and intravenous bisphosphonate therapies are equally effective in children with OI and are particularly effective in milder forms. The oral route is highly acceptable in children and has practical advantages over the intravenous route. As adults with cystic fibrosis (CF) have enjoyed incremental increases in longevity over the last few decades, they have also been suffering from low bone density and its clinical manifestations, fractures and kyphosis. We conducted a placebo-controlled, randomized, double-blinded trial of alendronate (10 mg/day orally) (n = 24) compared with placebo (n = 24) for 1 year in 48 patients to improve bone mineral density at the spine as the primary endpoint. All patients received 800 IU of cholecalciferol and 1,000 mg of calcium carbonate. Both groups were similar in age, sex, CF mutations, bone density T scores, renal function, and body mass index at study onset. The alendronate-treated patients gained (mean +/- SD) 4.9 +/- 3.0% and 2.8 +/- 3.2% bone density after 1 year versus placebo, which lost (mean +/- SD) 1.8 +/- 4.0% and 0.7 +/- 4.7%, in spine and femur bone density, respectively (p < or = 0.001 for the spine; p = 0.003 for the femur). Urine N-telopeptide, a bone resorption marker, levels declined in the treatment group more than in the control group (p = 0.002), consistent with the known antiresorptive effects of bisphosphonates. Alendronate was more effective than placebo in improving spine and femur bone mineral density and is a promising agent for the long-term prevention and management of bone disease in patients with CF. Bisphosphonates can prevent bone mineral density loss after renal transplantation, but their effect on trabecular mineralization and bone morphology, two key factors of bone stability, remains unknown.
                In a 6-month, randomized, placebo-controlled study, 20 kidney transplant recipients received either 4 mg zoledronic acid or placebo twice within 3 months after engraftment. At transplantation and after 6 months, mean trabecular calcium concentration and trabecular morphometry were measured in bone biopsies. Bone mineral density (BMD) of the femoral neck and the lumbar spine were evaluated by dual-energy x-ray absorptiometry, and serum biochemical markers of bone metabolism were determined monthly.
                Trabecular calcium content increased significantly in the zoledronic acid group, but remained unchanged in the placebo group. BMD at femoral neck showed no change in the zoledronic acid group, but decreased in the placebo group. BMD of the lumbar spine was increased in the zoledronic acid group without change in the placebo group. High-turnover bone disease resolved similarly in both groups, as evidenced by a significant decrease of eroded bone surface, osteoclast and osteoblast surface. Serologic markers of bone formation and resorption were significantly lower in zoledronic acid-treated patients throughout the study. Kidney transplant function was stable after zoledronic acid therapy.
                Our results show that administration of zoledronic acid improves the calcium content of cancellous bone after kidney transplantation. The beneficial effect of bisphosphonate therapy is further evidenced by an increase of lumbar spine BMD, and stabilization of femur BMD. In a prospective, controlled, and randomized clinical trial, we examined the effects of treatment with vitamin D (1,000 IU/d), calcium (1 g/d), and ethane-1-hydroxy-1,1-diphosphonate (EHDP; 7.5 mg/kg body weight) on vertebral bone mass in fourteen asthmatics undergoing long-term treatment with systemically applied corticosteroids. The extent of steroid-induced bone loss was judged by vertebral bone density of the lumbar spine measured by dual-photon absorptiometry as well as by vertebral crush fracture incidence examined by conventional X-ray. Results of the measurements before treatment and after six mo were compared with those of an untreated control group of nineteen asthmatics. Bone density increased during the observation period by 5% in the treated group, compared with a decrease of 4.3% in the untreated control group (p < 0.01). Moreover, in the treated group no radiologically visible new fractures occurred; in the control group new fractures were observed in four patients. There were no serious side effects of the applied drugs during the 6-mo period. Therefore, the combination of EHDP, calcium, and vitamin D appears to be a useful regimen for the management of steroid-induced bone loss in adult asthmatics. Osteogenesis imperfecta (OI) is a heritable disease of connective tissue, characterized by increased bone fragility. Bisphosphonates currently seems to be the most promising therapy, at least in children. We tested IV neridronate, an amino-bisphosphonate structurally similar to alendronate and pamidronate in adults with OI. Twenty-three men and 23 premenopausal women with OI were randomized to either iv neridronate (100 mg infused intravenously for 30 minutes every 3 months) or no treatment with a ratio of 2 to 1. Control patients were given the same bisphosphonate therapy at the end of the first year. Clinical evaluation included bone densitometry measurements using dual energy X-ray absorptiometry (DXA), fasting serum and urinary biochemistry every 6 months, and radiographs of the spine taken at baseline and after 12 and 24 months of follow-up. Spine and hip bone mineral density rose by 3.0 +/- 4.6% (SD) and by 4.3 +/- 3.9%, respectively, within the first 12 months of treatment, whereas small insignificant changes were observed in the control group. During the second year of follow-up, additional 3.91% and 1.49% increases were observed at the spine and hip, respectively. Markers of skeletal turnover significantly fell during neridronate treatment. Fracture incidence during neridronate treatment was significantly lower than before therapy and compared with controls. Neridronate iv infusions, administered quarterly, significantly increase bone mineral density and lowered the risk of clinical fracture in adults with OI. Bisphosphonate therapy seems to provide clinical benefits, not only to children with OI, but also to adult patients.
Oral and intravenous bisphosphonates increase bone mineral density in people with cystic fibrosis. Severe bone pain and flu-like symptoms may occur with intravenous agents. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids ameliorate or prevent these adverse events. Additional trials are also required to further assess gastrointestinal adverse effects associated with oral bisphosphonates. Trials in larger populations are needed to determine effects on fracture rate and survival.