Intravenous intermittent neridronate in the treatment of postmenopausal osteoporosis.

Bisphosphonates have been used with success in the treatment of osteoporosis, but oral therapy often lacks compliance. Here we report the results of clinical trial with aminobisphosphonate neridronate administered intravenously (i.v.). The study included 78 postmenopausal women with spine bone mineral density (BMD) at least -2.5 SD below peak. Patients were randomized to receive for 2 years either 50 mg i.v. neridronate bimonthly and 500 mg calcium plus 400 U vitamin D supplements daily (n=39) or calcium-vitamin D supplements alone (control group, n=39). Treatment was continued over 2 years with an additional 1 year follow-up of calcium-vitamin D supplements alone. Neridronate was well tolerated with the appearance of typical clinical signs of an acute phase reaction in only 3 of the patients after the first infusion. In the control group no significant changes in BMD or bone markers were observed. In the neridronate group BMD rose progressively at the spine rose up to 7.4% +/- 6.1% (SD) and at the femoral neck up to 5.8% +/- 8.2% (SD) at the end of the second year. In the succeeding follow-up these gains were maintained at both skeletal sites. Serum bone alkaline phosphatase (bone ALP) and serum type I collagen C-telopeptide (s-CTX) significantly decreased within 2 months. The bone ALP values reached a -35% plateau after 6 months, while s-CTX attained the lowest mean value (-47%) only by the end of the treatment with neridronate. Both bone markers returned almost to baseline values 1 year after treatment discontinuation. Treatment of postmenopausal osteoporosis with 50 mg i.v. neridronate bimonthly results in clinically relevant increases in BMD, among the largest so far observed with any other bisphosphonate.

Intravenous neridronate in adults with osteogenesis imperfecta.

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.

Alendronate for the treatment of osteoporosis in men.

The incidence of osteoporotic fracture in males is approximately one-third of that observed in women, but information on specific therapies is almost exclusively limited to bisphosphonate alendronate. The most important study with this compound included 241 men, randomized to receive either alendronate 10 mg/day or placebo. In another study 134 men were given either 10 mg alendronate or alfacalcidiol 1 microg/day. After 24 months, the treatment with alendronate bone mineral density (BMD) significantly increased in both studies by 7-10% at the lumbar spine and by 2.5-5.2% at the femoral neck. These changes were associated with decreases in vertebral fracture rate and in stature loss, both statistically significant when the data of the two trials were meta-analysed. The BMD changes after alendronate therapy were comparable to those observed in postmenopausal osteoporosis. This was confirmed in a trial specifically designed to compare alendronate efficacy in men and postmenopausal women with either primary or secondary osteoporosis. Gender-comparative efficacy data can also be inferred from clinical trials in glucocorticoid-induced osteoporosis of alendronate, risedronate, and etidronate, carried out in both women and men. By combining the results of all these trials, bisphosphonate efficacy in terms of both BMD changes and fracture incidence appears to be moderate in premenopausal women but quite obvious and comparable in males and postmenopausal women.

Transforming growth factor-beta1 gene polymorphism, bone turnover, and bone mass in Italian postmenopausal women.

Transforming growth factor beta1 (TGF-beta1) is abundant in bone and is an important regulator of the osteoclastic-osteoblastic interaction (coupling). The sequence variation, 713-8delC in the TGF-beta1 gene has previously been found to be associated with very low bone mass in osteoporotic women and with increased bone turnover in both osteoporotic and normal women. The possible association of this polymorphism with bone mass and bone turnover has now been investigated in 256 postmenopausal Italian women. A significant association of TGF-beta1 with bone mass was detected in the populations. Subjects carrying the sequence variation 713-8delC (Tt) genotype showed a significantly lower bone mineral density (BMD) at the hip than those without sequence variation in the genotype (TT). Individuals carrying the tt genotype have a more severe osteoporosis (P=0.0001 vs. TT and Tt genotypes). The frequency of the fragility fractures was significantly lower in individuals with TT genotype than in those with the Tt and tt genotypes (X2=21.9; P=0.006). Furthermore a significant association was found between 713-8delC and bone turnover. The results suggest a strong evidence for an association among the 713-8delC allele of the TGF-beta1 gene and the femoral BMD, the prevalence of osteoporotic fractures, and finally a high bone turnover in a sample of Italian postmenopausal women.

Urinary galactosyl-hydroxylysine in postmenopausal osteoporotic women: A potential marker of bone fragility.

Alterations of the collagen matrix, e.g., increased hydroxylation and glycosylation of lysyl residues in collagen I, were found in human osteoporotic bone, and it was suggested that they could alter the mechanical properties of skeleton. To test this hypothesis, we evaluated the content of galactosyl-hydroxylysine (GHYL) in bone collagen, as assessed by its urinary excretion, and related it to the occurrence of fracture. Two hundred and fifteen unselected postmenopausal women with osteoporosis were divided in two subgroups (comparable for age, age of menopause, bone mineral density, and biochemical parameters of bone turnover) on the basis of the history of fragility fracture; 115 patients had suffered no fracture and 100 patients had suffered one or more fractures 3 or more years before. Four urinary markers of bone turnover (hydroxyproline, cross-linked N-telopeptide, free deoxypyridoline, and GHYL) were evaluated in all patients. There was no difference between the two groups with regard to all the parameters studied except for GHYL, which was significantly higher in the group with a history of fracture (1.35 +/- 0.82 mmol/mol of creatinine [Cr] versus 1.03 +/- <0.48 mmol/mol Cr, p < 0.001); this marker did not correlate with other markers of bone remodeling in the fracture group, indicating a possible defect in bone collagen. In conclusion, provided that increased levels of urinary GHYL do reflect overglycosylation of hydroxylysine in bone collagen, the GHYL may be considered a marker of bone collagen quality. Our results, showing higher urinary GHYL in osteoporosis patients with fracture, seem to confirm this suggestion.