Intravenous zoledronic acid in postmenopausal women with low bone mineral density.

BACKGROUND: Bisphosphonates are effective agents for the management of osteoporosis. Their low bioavailability and low potency necessitate frequent administration on an empty stomach, which may reduce compliance. Gastrointestinal intolerance limits maximal dosing. Although intermittent intravenous treatments have been used, the optimal doses and dosing interval have not been systematically explored. METHODS: We studied the effects of five regimens of zoledronic acid, the most potent bisphosphonate, on bone turnover and density in 351 postmenopausal women with low bone mineral density in a one-year, randomized, double-blind, placebo-controlled trial. Women received placebo or intravenous zoledronic acid in doses of 0.25 mg, 0.5 mg, or 1 mg at three-month intervals. In addition, one group received a total annual dose of 4 mg as a single dose, and another received two doses of 2 mg each, six months apart. Lumbar-spine bone mineral density was the primary end point. RESULTS: There were similar increases in bone mineral density in all the zoledronic acid groups to values for the spine that were 4.3 to 5.1 percent higher than those in the placebo group (P<0.001) and values for the femoral neck that were 3.1 to 3.5 percent higher than those in the placebo group (P<0.001). Biochemical markers of bone resorption were significantly suppressed throughout the study in all zoledronic acid groups. Myalgia and pyrexia occurred more commonly in the zoledronic acid groups, but treatment-related dropout rates were similar to that in the placebo group. CONCLUSIONS: Zoledronic acid infusions given at intervals of up to one year produce effects on bone turnover and bone density as great as those achieved with daily oral dosing with bisphosphonates with proven efficacy against fractures, suggesting that an annual infusion of zoledronic acid might be an effective treatment for postmenopausal osteoporosis.

Genetic predisposition for adult lactose intolerance and relation to diet, bone density, and bone fractures.

UNLABELLED: Evidence that genetic disposition for adult lactose intolerance significantly affects calcium intake, bone density, and fractures in postmenopausal women is presented. PCR-based genotyping of lactase gene polymorphisms may complement diagnostic procedures to identify persons at risk for both lactose malabsorption and osteoporosis. INTRODUCTION: Lactase deficiency is a common autosomal recessive condition resulting in decreased intestinal lactose degradation. A -13910 T/C dimorphism (LCT) near the lactase phlorizin hydrolase gene, reported to be strongly associated with adult lactase nonpersistence, may have an impact on calcium supply, bone density, and osteoporotic fractures in the elderly. MATERIALS AND METHODS: We determined LCT genotypes TT, TC, and CC in 258 postmenopausal women using a polymerase chain reaction-based assay. Genotypes were related to milk intolerance, nutritional calcium intake, intestinal calcium absorption, bone mineral density (BMD), and nonvertebral fractures. RESULTS: Twenty-four percent of all women were found to have CC genotypes and genetic lactase deficiency. Age-adjusted BMD at the hip in CC genotypes and at the spine in CC and TC genotypes was reduced by -7% to -11% depending on the site measured (p = 0.04). LCT(T/C-13910) polymorphisms alone accounted for 2-4% of BMD in a multiple regression model. Bone fracture incidence was significantly associated with CC genotypes (p = 0.001). Milk calcium intake was significantly lower (-55%, p = 0.004) and aversion to milk consumption was significantly higher (+166%, p = 0.01) in women with the CC genotype, but there were no differences in overall dietary calcium intake or in intestinal calcium absorption test values. CONCLUSION: The LCT(T/C-13910) polymorphism is associated with subjective milk intolerance, reduced milk calcium intake, and reduced BMD at the hip and the lumbar spine and may predispose to bone fractures. Genetic testing for lactase deficiency may complement indirect methods in the detection of individuals at risk for both lactose malabsorption and osteoporosis.

Serum osteoprotegerin levels in patients after liver transplantation and correlation to bone turnover, bone mineral density and fracture status.

The aim of this cross sectional study was to evaluate the prevalence of osteoporosis, vertebral fracture status and possible risk factors of bone loss including serum osteoprotegerin, a novel key regulator of osteoclast proliferation and activity in the posttransplantation period. We investigated 15 patients (10 male, 5 female) 20 +/- 6 (SE) months after orthotopic liver transplantation (OLT). All patients received immunosuppressive therapy and non were on calcium and/or vitamin D supplements at the time of admission to our osteoporosis outpatient clinic. Examinations included a bone densitometry measurement at the femoral neck, a standardized spinal X-ray and a morning blood sample. According to WHO criteria, osteoporosis at the femoral neck was present in 67% (10/15) of the patients with a mean T-score of -2.55 +/- 0.35. Vertebral fractures were seen in 33% and the mean number of fractures was 2.4 per patient. Secondary hyperparathyroidism (33%), vitamin D deficiency (53%) as well as impaired renal function (47%) were frequent findings in the patients. Low serum calcium was associated with elevated PTH- (r = -0.75, p = 0.001), serum cross laps- (r = -0.61, p = 0.01), osteocalcin levels (r = -0.49, p = 0.05), was an independent predictor of femoral neck bone mass (r = 0.57, p = 0.02) and accounted for 36% of this variance. Similarly, serum magnesium levels were also independently correlated to femoral neck Z-scores (r = -0.68, p = 0.0005). Two-thirds of the patients had elevated serum cross-laps, osteocalcin and bone specific alkaline phosphatase levels reflecting increased bone turnover. Serum osteoprotegerin (OPG) in liver transplant recipients was not significantly different when compared to healthy, matched controls (84.7 +/- 6.6 vs. 97.3 +/- 9.4 pg/ml, p = 0.50) and similar when fractured/non-fractured or osteoporotic/non-osteoporotic patients were compared. Serum OPG was, however, significantly correlated to serum cross laps (r = 0.71, p = 0.003), osteocalcin (r = 0.63, p = 0.01), serum parathyroid hormone (r = 0.61, p = 0.01) and serum creatinine levels (r = 0.53, p = 0.04) and showed only a weak and non-significant correlation to femoral neck Z-scores (r = -0.38, p = 0.16). Multiple regression analysis revealed that serum OPG was correlated independently of PTH, serum calcium and creatinine to serum cross-laps concentrations (r = 0.63, p = 0.04). In summary, we found a high prevalence of osteoporosis and vertebral fractures in liver transplant recipients with many of the patients showing evidence of vitamin D deficiency, secondary hyperparathyroidism and accelerated bone turnover. We conclude that secondary hyperparathyroidism and possibly serum magnesium seems to contribute significantly to the changes in bone mass during the posttransplantation period. Serum OPG was not correlated to bone mass or fracture status in this cross sectional setting but was elevated together with other bone resorption and -formation markers.

Osteoprotegerin serum levels in women: correlation with age, bone mass, bone turnover and fracture status.

Pre-clinical data have shown that osteoprotegerin (OPG) inhibits osteoclast function and therefore plays an important role in bone remodelling. This study aimed to evaluate the clinical value of serum OPG. Do higher OPG serum levels reflect decreased bone resorption and perhaps higher bone mass in women? Serum OPG levels were measured in 177 healthy women (aged 17-85 years) and in 48 untreated patients (mean age 71 +/- 5) with established osteoporosis, and related to age, bone mass, markers of bone turnover and, in the case of patients with osteoporosis, to pre-existing vertebral fractures. In healthy women OPG levels showed a positive correlation with age (r = 0.25, p < 0.001) but not to bone mass or markers of bone turnover. In women with osteoporosis, however, there was a strong relationship between serum OPG and markers of bone turnover (serum c-terminal crosslinked telopeptides of thpe I collagen (sCTX): r = +0.82, p < 0.0001; osteocalcin (OC): r = +0.69, p < 0.0001), with patients who had higher levels of bone-turnover markers showing higher serum levels of OPG. After adjustment for bone mass and bone markers, patients with pre-existing vertebral fractures had significantly lower serum OPG levels than patients without fractures (57 +/- 8 vs. 97 +/- 10 pg/ml, [mean +/- SE], p < 0.01). The age-dependent increase of OPG as an antiresorptive factor may reflect an insufficient paracrine mechanism of bone cells to compensate for bone loss in older age. In patients with osteoporosis, however, OPG correlated strongly with markers of bone turnover; this may point toward a higher level of RANKL/OPG expression in these patients. Finally, low OPG serum levels seem to be associated with vertebral fractures. We hypothesise that low OPG levels in preset conditions of bone turnover may indicate a higher risk of fracture in patients with osteoporosis.

Hypovitaminosis D, impaired bone turnover and low bone mass are common in patients with peripheral arterial disease.

Hypovitaminosis D is common in patients with peripheral arterial disease (PAD). Subsequent secondary hyperparathyroidism and osteomalacia contribute to bone pain and myalgias, and so aggravate clinical symptoms of claudication. We evaluated 95 out of 297 patients with angiographically confirmed PAD stages II (pain in the calves and/or thighs only during exercise) or IV (history of, or presence of local ulcers) and compared them with 44 matched healthy controls regarding their medical history, bone density measurements of the femoral neck and calcaneal bone ultrasound. Bone pain, myalgias and mobility restriction as well as routine laboratory parameters, serum vitamin D [25(OH)D], crosslaps (CTX), parathyroid hormone (PTH), osteocalcin (OC) and alkaline phosphatase (AP) were recorded and analysed. 25(OH)D was significantly lower in PAD IV patients (9.6+/-4.6 ng/ml, P<0.0001) as compared to PAD II stages and controls (19.0+/-7.6 and 19.1+/-9.1 ng/ml), paralleled by lower serum calcium [2.24+/-0.02 mmol/l, P=0.0002 versus PAD II (2.36+/-0.02) and P<0.0001 versus controls (2.39+/-0.02)] and higher iPTH serum levels (66.3+/-3.6 pg/ml, P<0.0001) as compared to PAD II patients (45.3+/-3.5) and healthy controls (38.5+/-2.4). Alkaline phosphatase and serum crosslaps values were significantly higher and age-adjusted bone density and bone ultrasound measurements significantly lower in PAD IV patients, who were also twice as likely to have bone pain and myalgias as PAD II patients. Bone ultrasound measurements correlated significantly with both clinical severity and pain as well as serological parameters of bone metabolism. Underlying PAD has a significant impact on bone density and metabolism as well as on bone and muscular pain. Patients with PAD are at high risk for osteoporosis and osteomalacia and should be regularly monitored and treated for their vitamin D deficiencies.

Vitamin D deficiency and secondary hyperparathyroidism are common complications in patients with peripheral arterial disease.

OBJECTIVE: To investigate via the vitamin D status whether patients with peripheral arterial disease (PAD) tend to develop vitamin D deficiency that in turn influences their clinical symptoms. DESIGN: Cross-sectional. SETTING: University hospital. PATIENTS AND PARTICIPANTS: Three hundred twenty-seven patients were evaluated; subjects with secondary causes of bone disease or bone active medication were excluded. One hundred sixty-one patients with either PAD stage II (n = 84) or stage IV (n = 77) were enrolled and compared to 45 age- and sex-matched healthy controls. MEASUREMENTS AND MAIN RESULTS: All patients underwent determinations of serum chemistry, 25-hydroxyvitamin D (vitamin D3) intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), and osteocalcin and were further stratified according to an individual restriction score into 3 groups: mildly, moderately, or severely restricted in daily life due to the underlying disease. Patients with PAD IV showed significantly lower vitamin D3 (P =.0001), and calcium (P =.0001) values and significantly higher iPTH (P =.0001), osteocalcin (P =.0001) and ALP (P =.02) levels as compared to patients with PAD II. Patients considering themselves as severely restricted due to the underlying disease showed lower vitamin D3 and higher iPTH levels than those who described only a moderate (vitamin D3: P <.001; iPTH: P <.01) or mild (vitamin D3: P <.001; iPTH: P <.001) restriction in daily life. CONCLUSION: Patients with PAD IV, especially those who feel severely restricted due to the disease, are at high risk of developing vitamin D deficiency, secondary hyperparathyroidism, and ultimately osteomalacia due to immobilization and subsequent lack of exposure to sunlight, all of which in turn lead to further deterioration. Monitoring of vitamin D metabolism and vitamin D replacement therapy could be a simple, inexpensive approach to mitigating clinical symptoms and improving quality of life in patients with advanced PAD.

Vitamin D receptor initiation codon polymorphism, bone density and inflammatory activity of patients with ankylosing spondylitis.

OBJECTIVES: Osteoporosis is a common finding in ankylosing spondylitis (AS) and may contribute to spinal deformity and bone pain. Bone metabolism as well as inflammatory processes are influenced by the vitamin D receptor gene (VDR). We investigated initiation codon ( FokI) and 3'UTR ( BsmI) polymorphisms of the VDR for whether there could be an association with bone mineral density (BMD) in relation to bone metabolism or inflammatory activity in patients with AS. METHODS: In this study, 104 patients with AS (m/w 71/33, mean age 41+/-12 years) were investigated for their lumbar and femoral BMD by DEXA and in part by QCT measurements and compared to 54 healthy controls. Disease activity indices, serum markers of bone metabolism and inflammation were recorded. FokI and BsmI polymorphisms of the VDR were genotyped using genomic DNA from peripheral leukocytes with present or absent restriction sites defined as alleles " f" and " b" or " F" and " B," respectively. RESULTS: In male AS patients, FokI genotypes were significantly associated with spinal but not with femoral BMD values ( P=0.01) as independent predictors of low BMD, which was also influenced by BMI, and inflammatory and pain indices. CRP and ESR values were also significantly associated with FokI genotypes. BMD in female patients showed no significant association with either FokI or BsmI genotypes of the VDR. CONCLUSION: This is the first evidence that the VDR gene may be involved in BMD differences, bone metabolism and inflammatory processes in ankylosing spondylitis. A possible interaction of the vitamin D system, cytokines and bone could define new diagnostic and therapeutic implications in ankylosing spondylitis.