Growth hormone secretion and bone mineral density in prepubertal black and white boys.

Racial differences in bone mineral density (BMD) appear to account in part for racial differences in the incidence of osteoporosis and fractures. We previously reported that the greater BMD in adult blacks compared with whites is associated with a higher serum 17 beta-estradiol and greater secretion of growth hormone (GH) in men but not women. To determine whether these racial differences occur in prepubertal boys, we measured spontaneous overnight GH secretion, serum testosterone, 17 beta-estradiol, IGF-I, and IGFBP3, IGF-I/ IGFBP3 ratio, BMD of the total body, forearm, lumbar spine, trochanter, and femoral neck, and lean body mass and body fat in 14 healthy black and 16 white boys ages 6-7 years. Measurements of GH were obtained at 20-minute intervals for 12 hours. Results were analyzed by deconvolution and are expressed as mean +/- SE. Whereas BMD of the hip (0.755 +/- 0.020 vs 0.663 +/- 0.021 g/cm(2), P = 0.0037), trochanter (0.617 +/- 0.014 vs 0.552 +/- 0.018 g/cm(2), P = 0.0102) and femoral neck (0.710+/-0.018 vs 0.6381 +/- 0.021 g/cm(2), P = 0.0157) were significantly greater in black compared with white boys, BMD of the total body (0.768 +/- 0.010 vs 0.741 +/- 0.012 g/cm(2), NS), forearm (0.405 +/- 0.010 vs 0.380 +/- 0.008 g/cm(2), NS), and lumbar spine (0.612 +/- 0.013 vs 0.609 +/- 0.021 g/cm(2), NS) was not different in the two groups. Stepwise regression analysis showed significant correlations between BMD and race at each skeletal site except the lumbar spine and trochanter. Deconvolution analysis revealed no racial difference in any of the GH measurements. Whereas serum testosterone, serum 17 beta-estradiol, and serum IGF-I were not different, serum IGFBP-3 was higher and the molar ratio of serum IGF-l/IGFBP-3 was lower in white than in black males. In summary, prepubertal BMD is higher in black than in white males at the hip, trochanter, and femoral neck, and the racial difference does not result from differences in secretion of GH.

Treatment and prevention of osteoporosis: future directions.

Osteoporosis is an important disease because of its prevalence and because it is associated with significant morbidity and mortality. As a consequence, development of new means of treating the disease is a major goal of drug companies. A number of new scientific discoveries have provided new rationales for development of new drugs that act either to inhibit bone resorption or to stimulate bone formation. These new drugs should greatly expand the therapeutic approach that can be used for treatment of this common disorder in the individual patient.

Effects of race on diurnal patterns of renal conservation of calcium and bone resorption in premenopausal women.

Previous studies showed differences in bone and mineral metabolism in African-Americans and Caucasians: reductions in serum 25-hydroxyvitamin D [25(OH)D], urinary calcium and skeletal remodeling and moderate secondary hyperparathyroidism. Diurnal studies were carried out in 7 African-American and 7 white normal premenopausal women matched for age, weight and height to further characterize these racial differences in calcium homeostasis. Serum 25(OH)D was significantly lower and serum intact parathyroid hormone (PTH) was significantly higher in the African-American compared with the white women, whereas serum total calcium, Ca2+, phosphorus and 1,25-dihydroxyvitamin D [1,25(OH)2D] were not different in the two groups. Serum intact PTH increased significantly at night in the white women and did not change in the African-American women. Urinary calcium was 47% lower in the African-American than in the white women during the day but was not different at night. Urinary calcium declined at night by 53% in the white women and by 40% in the African-American women. Stepwise multivariate analysis showed that determinants of urinary calcium were mean 24 h serum intact PTH and serum Ca2+ in the two groups together, mean 24 h serum intact PTH, body mass index (BMI) and serum 25(OH)D in the white women, and BMI in the African-American women. Urinary N-telopeptide of type I collagen, a marker of bone resorption, increased by over 60% at night in both groups and was 25% lower in African-American compared with white women, but the difference was not statistically different. Urinary free deoxypyridinoline also increased at night in both groups and was not racially different. Thus, African-American women show higher serum intact PTH and greater conservation of calcium than white women throughout the day. In both groups, maintenance of serum calcium at night is achieved by increased bone resorption and renal conservation of calcium.

ApaI polymorphisms of the vitamin D receptor predict bone density of the lumbar spine and not racial difference in bone density in young men.

A number of previous investigations showed significant associations between polymorphisms of the vitamin D receptor (VDR) gene and bone mineral density (BMD). BMD is influenced by hormones and the rate of skeletal remodeling. A study was performed to investigate the possible relationship between Apa I, Bsm I, Taq I, and Fok I polymorphisms of the VDR gene and serum 1,25-dihydroxyvitamin D (1,25[OH]2D), osteocalcin, and propeptide of type I collagen (PICP)-markers of bone turnover, total body calcium, and BMD of the total body, radius, lumbar spine, trochanter, and femoral neck-in 39 young adult black men of 20 to 40 years of age and 44 age-, height-, and weight-matched white men. The distribution of each of the four alleles of the VDR genotypes was similar in the two racial groups. The Apa I VDR genotype was associated with serum PICP (P =.0494) but not with serum 1,25(OH)2D or serum osteocalcin. A significant association between the Apa I VDR genotype and BMD of the lumbar spine (P =.0291) was also observed. However, the Bsm I, Taq I, and Fok I genotypes were not significantly associated with BMD or serum osteocalcin, PICP, or 1,25(OH)2D. Multivariate stepwise analysis indicated that (1) the Apa I VDR genotype was associated with BMD of the lumbar spine in the two groups together; with total body calcium and BMD of the total body, radius, trochanter, and femoral neck in the black men; and with BMD of the radius in the white men; analysis also indicated that (2) race was significantly associated with total body calcium and BMD of the total body, lumbar spine, and femoral neck. In summary, the Apa I VDR genotype is associated with serum PICP and BMD at a number of sites but does not contribute to or account for racial differences in BMD in young adult men.

Advances in the treatment of osteoporosis.

Drugs used to treat osteoporosis act either by inhibiting bone resorption or stimulating bone formation. Osteoclast formation and bone resorption require cell-to-cell contact between osteoblasts and osteoclast precursors and osteoclasts in the marrow. Interaction between the receptor for activation of nuclear factor kappa B (RANK) on the surface of preosteoclasts and osteoclasts and RANK ligand on the surface of osteoblasts is required to stimulate osteoclast formation and activation. Binding of the RANK ligand to its receptor and osteoclastogenesis are prevented by osteoprotegerin (OPG), a decoy receptor produced by osteoblasts and marrow stromal cells. Thus, interference in binding of the RANK ligand to RANK by OPG determines the rate of bone resorption. Antiresorptive drugs such as estrogen, raloxifene, bisphosphonates, salmon calcitonin, and osteoprotegerin increase bone mass by inhibiting osteoclast function and bone resorption. Osteoprotegerin is more potent since it also inhibits osteoclast formation. Raloxifene, a selective estrogen receptor modulator (SERM), is a member of a class of compounds that act through estrogen receptors and are agonists for bone, antagonists for breast and uterine tissue and may be cardioprotective. The drug was shown to prevent vertebral fractures. Alendronate and bisphosphonates are the only antiresorptive drugs that have been shown to decrease fracture rates for the hip in addition to spine and other sites. Bone morphogenetic proteins stimulate bone formation at local sites and are being developed to stimulate fracture healing. Parathyroid hormone (1-34) stimulates osteoblastic bone formation, markedly increases bone mass, prevents vertebral fractures and is under development to treat osteoporosis.

Clinical use of biochemical markers of bone remodeling: current status and future directions.

Biochemical markers of bone turnover provide a means of evaluating skeletal dynamics that complements static measurements of bone mineral density (BMD). This review evaluates the use of commercially available bone turnover markers as aids in diagnosis and monitoring response to treatment in patients with osteoporosis. High within-person variability complicates but does not preclude their use. Elevated bone resorption markers appear to be associated with increased fracture risk in elderly women, but there is less evidence of a relationship between bone formation markers and fracture risk. The critical question of predicting fracture efficacy with treatment has not been answered. Changes in bone markers as currently determined do not predict BMD response to either bisphosphonates or hormone replacement therapy. Single measurements of markers do not predict BMD cross-sectionally (except possibly in the very elderly), or change in BMD in individual patients, either treated or untreated. On the other hand, research applications of bone turnover markers are of value in investigating the pathogenesis and treatment of bone diseases. Markers have potential in the clinical management of osteoporosis, but their use in this regard is not established. Additional studies with fracture endpoints and information on negative and positive predictive value are needed to evaluate fully the utility of bone turnover markers in individual patients.

Comparison of alendronate and intranasal calcitonin for treatment of osteoporosis in postmenopausal women.

This study compared the effects of oral alendronate and intranasal calcitonin for treatment of osteoporosis in postmenopausal women. Women at least 5 yr postmenopause (n = 299) were randomized to either 10 mg alendronate, matching alendronate placebo, or open-label intranasal calcitonin 200 IU daily for 12 months. Hip and spine bone mineral density (BMD) and markers of bone turnover were measured, and safety and tolerability were assessed. Alendronate produced greater increases in BMD than calcitonin at 12 months at the lumbar spine (5.16% vs. 1.18%; P < 0.001), trochanter (4.73% vs. 0.47%; P < 0.001), and femoral neck (2.78% vs. 0.58%; P < 0.001). Changes in BMD with calcitonin were greater than with placebo at the femoral neck, but were not different from placebo at either the trochanter or lumbar spine. Greater decreases in bone turnover were seen with alendronate than with calcitonin (serum bone-specific alkaline phosphatase, 43% vs. 9%, P < 0.001; urinary N-telopeptide, 62% vs. 11%, P < 0.001). Similar percentages of patients in each group reported an adverse experience during the study. We conclude that, in postmenopausal women with osteoporosis, 12 months of therapy with alendronate produced significantly greater increases in BMD of the hip and spine and greater decreases in bone turnover than intranasal calcitonin.

Steroid receptor co-activator-1 mediates 1,25-dihydroxyvitamin D(3)-stimulated alkaline phosphatase in human osteosarcoma cells.

For steroid hormone function to occur, nuclear receptors interact with a series of coactivators including steroid receptor coactivator-1 (SRC-1). The SRC-1 binds the vitamin D receptor (VDR) in the presence of ligand in an activation function 2 (AF-2)-dependent manner. In order to understand the role of this interaction in 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]-mediated gene expression, the level of SRC-1 expression was altered in MG-63 cells. Previous studies had demonstrated that MG-63 cells express the VDR and that 1,25(OH)(2)D(3) regulates expression of alkaline phosphatase (ALP). Analysis of MG-63 cells demonstrated that SRC-1 is expressed. A full-length cDNA coding for SRC-1 was inserted in antisense orientation into an expression vector (anti-SRC-1). The MG-63 cells were transfected with anti-SRC-1 or mock vector and stable transformants were selected. Western blot analysis showed a 95% reduction in SRC-1 protein as compared with mock cells. We determined the effect of normal and reduced SRC-1 expression in MG-63 cells on 1,25(OH)(2)D(3)-mediated stimulation of ALP. Whereas 10(-8) M 1,25(OH)(2)D(3) produced a 3.6-fold stimulation in ALP in mock cells expressing normal levels of SRC-1, it did not alter ALP in cells expressing reduced levels of SRC-1. Thus, SRC-1 is required for 1,25(OH)(2)D(3)-mediated gene expression of ALP by human MG-63 cells.

Collagen N-telopeptide excretion in men: the effects of age and intrasubject variability.

Biochemical markers of bone resorption are useful for evaluating metabolic bone diseases. A three-center study was performed in 253 men, 21-86 yr of age, to determine the normal range of urinary N-telopeptide of type I collagen (NTX/creatinine) in a nonfasting, second void, morning specimen, to define the biological variability and to examine the relationship between NTX/creatinine and age. Men with disorders or taking medications known to alter bone turnover, or with a serum creatinine level greater than 2 mg/dL were excluded. Results are expressed as nanomoles of bone collagen equivalents (BCE) per mmol creatinine. In a subset of individuals over age 30 yr, additional second void morning urine specimens were obtained at 2, 3, and 4 days (short term study) and at 2, 3, and 4 months (long term study) after the first specimen. After collection, samples were shipped to one laboratory for analysis. Multiple samples from the same subject were analyzed in separate assays. It was found that urinary NTX/ creatinine was significantly higher in 45 men, aged 21-30 yr, than in 206 men, aged 31-86 yr (48 +/- 22 vs. 33 +/- 15 nmol/L BCE/mmol/L creatinine; P < 0.00001). Values did not otherwise change with age. The range of values in men aged 21-30 yr was 4-92 nmol/L BCE/mmol/L creatinine. The range for men over age 30 yr was 3- 63 nmol/L BCE/mmol/L creatinine, essentially the same as that previously reported for premenopausal women. The coefficient of variation was determined in each individual for the short term (n = 36) and long term studies (n = 35) and averaged 18% and 19%, respectively. There was no correlation between short term and long term coefficient of variations. In summary, urinary NTX/creatinine is higher in men aged 21-30 yr than in men over age 30 yr and may reflect continued skeletal maturation. Intrasubject variability of urinary NTX/creatinine in short term and long term studies has been defined for clinical purposes.

Evidence that ibuprofen antagonizes selective actions of estrogen and tamoxifen on rat bone.

Studies were performed to determine if the nonsteroidal anti-inflammatory drug ibuprofen alters bone and mineral metabolism in female rats. In experiment 1, four groups of growing rats underwent either sham operation or ovariectomy (OVX). One week later, controlled-release pellets with ibuprofen or placebo were implanted subcutaneously at the back of the neck. Following 3 weeks of treatment, rats were sacrificed and blood and bone samples were removed for serum assays and histomorphometric analysis. Body growth rate and the static cortical bone measurements made at the tibial diaphysis did not change in response to OVX. OVX, however, did increase radial bone growth, lowered serum 17beta-estradiol, reduced uterine weight, and decreased the cancellous bone area of the tibial metaphysis in the rats. Ibuprofen did not alter serum 17beta-estradiol or uterine weight but reduced radial bone growth as well as cancellous bone area of the tibial metaphysis in both sham-operated and OVX animals. In experiments 2 and 3, we tested the influence of ibuprofen on the effects of the tissue-selective estrogen agonist tamoxifen and of exogenous 17beta-estradiol in the OVX rat. Ibuprofen completely blocked the effects of tamoxifen and partially blocked the effects of 17beta-estradiol to prevent cancellous osteopenia. In contrast, ibuprofen did not influence the effects of tamoxifen and 17beta-estradiol to reduce radial bone growth. Besides the skeletal effects, ibuprofen suppressed estrogen-induced uterine growth. Our data suggest that ibuprofen blocks selective estrogen receptor-mediated activities in the rat.

Orchiectomy markedly reduces the concentration of the three isoforms of transforming growth factor beta in rat bone, and reduction is prevented by testosterone.

Available evidence indicates that transforming growth factor beta (TGFbeta) is produced by bone cells, that production is enhanced by testosterone and dihydrotestosterone, and that TGFbeta is an important modulator of bone formation, induction, and repair. To determine the relative concentrations of isoforms of skeletal TGFbeta, whether orchiectomy alters the concentration of TGFbeta in long bones, and whether alteration is prevented by testosterone replacement, male Sprague-Dawley rats were either sham-operated and given placebo (n = 20) or orchiectomized and given either placebo (n = 20) or 100 mg testosterone (n = 20) by slow-release pellets implanted sc at the back of the neck and killed at 6 weeks. Orchiectomy did not change serum calcium and lowered serum testosterone and serum phosphorus; these reductions were prevented by testosterone replacement. TGFbeta1 in skeletal extracts was much more abundant than TGFbeta2 or TGFbeta3. Orchiectomy reduced skeletal TGFbeta by over 80 percent, and reduction was prevented by testosterone replacement. The relative abundance of the three isoforms of TGFbeta in bone was not influenced by orchiectomy or testosterone replacement, and skeletal messenger RNA of TGFbeta1 and TGFbeta2 was not altered 4 weeks after orchiectomy. Messenger RNA for TGFbeta3 was below the limits of detection. Thus, testosterone deficiency markedly diminishes skeletal TGFbeta, and reduction is prevented by testosterone replacement. The findings support the hypothesis that testosterone and TGFbeta are required for maintenance of the skeleton in male rats.

Mapping the domains of the interaction of the vitamin D receptor and steroid receptor coactivator-1.

The vitamin D receptor (VDR) binds to the vitamin D response element (VDRE) and mediates the effects of the biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], on gene expression. The VDR binds to the VDRE as a heterodimeric complex with retinoid X receptor. In the present study, we have used a yeast two-hybrid system to clone complementary DNA that codes for VDR-interacting protein(s). We found that the human steroid receptor coactivator-1 (SRC-1) interacts with the VDR in a ligand-dependent manner, as demonstrated by beta-galactosidase production. The interaction of the VDR and the SRC-1 takes place at physiological concentrations of 1,25(OH)2D3. A 48.2-fold stimulation of beta-galactosidase activity was observed in the presence of 10(-10) M 1,25-(OH)2D3. In addition, a direct interaction between the ligand-activated glutathione-S-transferase-VDR and 35S-labeled SRC-1 was observed in vitro. Deletion-mutation analysis of the VDR established that the ligand-dependent activation domain (AF-2) of the VDR is required for the interaction with SRC-1. One deletion mutant, pGVDR-(1-418), bound the ligand but failed to interact with the SRC-1, whereas another deletion mutant, pGVDR-(1-423), bound the ligand and interacted with the SRC-1. We demonstrated that all the deletion mutants were expressed as analyzed by a Gal4 DNA-binding domain antibody. Deletion mutation analysis of the SRC-1 demonstrated that 27 amino acids (DPCNTNPTPMTKATPEEIKLEAQSQFT) of the SRC-1 are essential for interaction with the AF-2 motif of the VDR.

Vitamin D metabolism is altered in Asian Indians in the southern United States: a clinical research center study.

Asian Indians who immigrate to northern Europe have lower serum 25-hydroxyvitamin D [25(OH)D] than Caucasians, and they develop vitamin D deficiency, rickets, and osteomalacia. We investigated vitamin D metabolism, the effects of 25(OH)D3 on vitamin D metabolism and activity of 25(OH) D-24-hydroxylase, the rate-limiting enzyme for degradation of 25(OH)D, from cultured skin fibroblasts of Asian Indians and compared them with cultured skin fibroblasts of Caucasians in the southern United States. Normal subjects, ages 20-40 yr, were admitted to a metabolic ward for 2.5 days and given a daily diet containing 400 mg calcium and 900 mg phosphorus. Serum vitamin D, serum 25(OH)D, urinary calcium, and urinary phosphorus were significantly lower, whereas serum immunoreactive intact parathyroid hormone (PTH) and serum 1,25-dihydroxyvitamin D [1,25(OH)2D] were significantly higher in Asian Indians than in Caucasians. Administration of 25(OH)D3 increased serum 25(OH)D and urinary calcium but did not change serum PTH or serum 1,25(OH)2D in Asian Indians. In cultured skin fibroblasts, Emax and Vmax of 25(OH)D-24-hydroxylase activity were significantly higher in Asian Indians. In summary, in Asian Indians serum vitamin D and 25(OH)D are markedly reduced, altered vitamin D metabolism is only partially reversed by 25(OH)D3, and 25(OH)D-24-hydroxylase activity in cultured skin fibroblasts is markedly increased. Thus, Asian Indians residing in the U.S. are at risk for developing vitamin D deficiency, rickets, and osteomalacia.

Increments in bone mineral density of the lumbar spine and hip and suppression of bone turnover are maintained after discontinuation of alendronate in postmenopausal women.

PURPOSE: Previously we have reported a significant increase in bone mineral density (BMD) of the spine and the hip and reductions in biochemical indices of bone turnover in postmenopausal women with osteoporosis treated with alendronate at various doses over 1 to 2 years. We have followed BMD and biochemical parameters in these patients for 1 or 2 years after discontinuation of alendronate to determine resolution of alendronate effects. PATIENTS AND METHODS: Participants received daily oral doses of placebo, 5 or 10 mg of alendronate for 2 years, or 20 or 40 mg of alendronate for 1 year followed by 1 year of placebo. No treatment was given in the third year of study. RESULTS: Lumbar spine BMD changes in the 5- and 10-mg groups (-1.4 and -0.4%) were similar to those in the placebo group (-1.2%) 1 year after discontinuation of drug and lumbar spine BMD changes in the 20- and 40-mg groups (-1.2% and 0.8%) were similar to those in the placebo group (-0.9%) 2 years after discontinuation of drug. BMD of the total hip followed the same pattern of resolution. The difference in BMD between alendronate and placebo groups at the end of alendronate treatment was maintained up to 2 years. Residual reductions in the bone resorption markers urinary deoxypyridinoline (D-Pyr) and collagen type 1 cross-linked N telopeptides and the bone formation markers serum bone-specific alkaline phosphatase and osteocalcin remained for 1 year after discontinuation of 5 and 10 mg of alendronate and for 2 years after discontinuation of 20 and 40 mg of alendronate, other than return of D-Pyr to baseline 1 year after cessation of treatment with the 5- and 10-mg doses. CONCLUSIONS: A residual decrease in bone turnover may be found up to 2 years after discontinuation of alendronate. Accelerated bone loss is not observed when treatment is discontinued. However, continuous therapy with alendronate is required to achieve a continuous gain in BMD.

Increased serum 1,25-dihydroxyvitamin D after growth hormone administration is not parathyroid hormone-mediated.

To assess the effects of growth hormone (GH) on serum 1,25-dihydroxyvitamin D [1,25(OH)2D], we performed the following prospective crossover study in six healthy, young, adult, white men. During each of two admissions for 2 1/2 days to a general clinical research center, subjects were placed on a daily dietary calcium intake of 400 mg. Serum calcium, phosphorus, 1,25(OH)2D, immunoreactive intact parathyroid hormone (PTH), insulin-like growth factor I (IGF-I), IGF binding protein 3 (IGFBP3), tubular reabsorption of phosphate (TMP/GFR) were measured. Recombinant human GH (rhGH, Humatrope) (25 microg/kg/day subcutaneously for 1 week) was administered prior to and during one of the admissions. Results are expressed as mean +/- SEM. Whereas serum 1,25(OH)2D (58.9 +/- 7.7 versus 51.6 +/- 7.4 pg/ml, P< 0.01), serum phosphorus (4.5 +/- 0.1 versus 3.7 +/- 0.1 mg/dl, P < 0.01), TRP (92.0 +/- 0.5 versus 87.8 +/- 0.7 mg/dl, P < 0.005), TMP/GFR (4.6 +/- 0.1 versus 3.5 +/- 0.2, P < 0.005), and urinary calcium (602 +/- 49 versus 346 +/- 25 mg/day, P < 0.001) increased significantly, serum PTH decreased significantly (19.9 +/- 1.9 versus 26.8 +/- 4.0 pg/ml, P < 0.05) and serum calcium did not change when subjects received rhGH. These findings indicate that in humans, GH affects serum 1,25(oh)2D independently of circulating PTH and that this effect is mediated by IGF-I. We propose, therefore, that one potential mechanism by which GH stimulates increases in bone mass is via modest increases in serum 1,25(OH)2D.

Bone and mineral metabolism in African Americans.

Important differences exist in the metabolism of bone and mineral and the vitamin D endocrine system between whites and African Americans and include rate o f skeletal remodeling, bone mass, and vitamin D metabolism. A higher bone mineral density (BMD) in African Americans is associated with a diminished incidence o f osteoporosis and fractures. Serum 17beta-estradiol and the rate of GH secretion are higher in black than in white men, but there is no racial difference in women in this regard. The mechanisms for reduced rate o f skeletal remodeling and for greater BMD in blacks are not known, but diminished rate of skeletal remodeling could be a contributing factor for greater bone mass. Reduction in serum 25-hydroxyvitamin D in blacks is attributed to increased skin pigment and to diminished dermal production of vitamin D(3) and consequent decreased hepatic synthesis o f the metabolite. There is no evidence that alteration of the vitamin D endocrine system contributes to or is responsible for racial differences in skeletal remodeling and bone mass. Black infants, however, are at risk for developing vitamin D-deficient rickets, particularly when breast-fed.

Bisphosphonates in the treatment of osteoporosis.

Bisphosphonates are compounds derived from pyrophosphate, a byproduct of cellular cleavage of adenosine triphosphate (ATP), and are resistant to alkaline phosphatase by virtue of replacement of oxygen by carbon. The high affinity of the P-C-P structure for hydroxyapatite accounts for deposition in bone. Modification of the two side chains of carbon alters the potency of the drugs. Of those that have either completed or are undergoing clinical trials, the order of increasing potency for inhibition of bone resorption is etidronate, clodronate, tiludronate, pamidronate, alendronate, residronate and ibandronate (potency range: 1 to 10,000). Less than 5% of bisphosphonates are absorbed and the half life is a few hours. The drugs must be given on an empty stomach because food and beverages interfere with gastrointestinal absorption. Of the absorbed fraction, as much as 60% is taken up by the skeleton and the remainder is excreted unchanged in the urine. Etidronate, tiludronate, residronate, and alendronate are given orally, clodronate intravenously, and pamidronate and ibandronate by either route. At lower concentrations, bisphosphonates inhibit osteoclatic bone resorption, whereas at higher concentrations they may inhibit mineralization and cause osteomalacia. Inhibition of mineralization diminishes with increasing potency. In postmenopausal women, etidronate and alendronate for 3 yr were shown to inhibit bone resorption, increase bone mineral density (BMD) of the lumbar spine and hip, and prevent fractures without producing osteomalacia. Bone formation also is reduced as a consequence of diminished bone resorption but reduction is less than the reduction of bone resorption. In higher doses bisphosphonates may cause upper gastrointestinal disturbances but in recommended doses they generally are well tolerated and have an excellent safety profile.