Robert W. Downs

Effect of Oral Alendronate on Bone Mineral Density and the Incidence of Fractures in Postmenopausal Osteoporosis

BACKGROUND Postmenopausal osteoporosis is a serious health problem, and additional treatments are needed. METHODS We studied the effects of oral alendronate, an aminobisphosphonate, on bone mineral density and the incidence of fractures and height loss in 994 women with postmenopausal osteoporosis. The women were treated with placebo or alendronate (5 or 10 mg daily for three years, or 20 mg for two years followed by 5 mg for one year); all the women received 500 mg of calcium daily. Bone mineral density was measured by dual-energy x-ray absorptiometry. The occurrence of new vertebral fractures and the progression of vertebral deformities were determined by an analysis of digitized radiographs, and loss of height was determined by sequential height measurements. RESULTS The women receiving alendronate had significant, progressive increases in bone mineral density at all skeletal sites, whereas those receiving placebo had decreases in bone mineral density. At three years, the mean (+/- SE) differences in bone mineral density between the women receiving 10 mg of alendronate daily and those receiving placebo were 8.8 +/- 0.4 percent in the spine, 5.9 +/- 0.5 percent in the femoral neck, 7.8 +/- 0.6 percent in the trochanter, and 2.5 +/- 0.3 percent in the total body (P < 0.001 for all comparisons). The 5-mg dose was less effective than the 10-mg dose, and the regimen of 20 mg followed by 5 mg was similar in efficacy to the 10-mg dose. Overall, treatment with alendronate was associated with a 48 percent reduction in the proportion of women with new vertebral fractures (3.2 percent, vs. 6.2 percent in the placebo group; P = 0.03), a decreased progression of vertebral deformities (33 percent, vs. 41 percent in the placebo group; P = 0.028), and a reduced loss of height (P = 0.005) and was well tolerated. CONCLUSIONS Daily treatment with alendronate progressively increases the bone mass in the spine, hip, and total body and reduces the incidence of vertebral fractures, the progression of vertebral deformities, and height loss in postmenopausal women with osteoporosis.

Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein.

Abstract Pseudohypoparathyroidism type I is characterized by resistance (defined as a deficient urinary cAMP response) to parathyroid hormone and, in most cases, hypocalcemia and hyperphosphatemia. Many patients with pseudohypoparathyroidism type I snow a peculiar somatic phenotype termed Albrights hereditary osteodystrophy, but patients without this feature who show identical parathyroid hormone resistance have been described. Parathyroid hormone resistance in pseudohypoparathyroidism type I has been attributed to a defective parathyroid hormone receptor-adenylate cyclase complex. Recent studies have demonstrated deficient activity of the guanine nucleotide regulatory protein (G unit) of adenylate cyclase in many patients with Pseudohypoparathyroidism. Since the G unit is common to all tissues, as opposed to hormone receptors, which are tissue specific, a defective G unit should lead to resistance to multiple hormones that act by stimulating adenylate cyclase. To test this hypothesis, we studied erythrocyte G unit activity and clinical endocrine function in 29 patients with pseudohypoparathyroidism type I. Thirteen patients had deficient erythrocyte G unit activity (43 ± 9 percent of control [mean ± 1 SD]); 16 patients had normal G unit activity (92 ± 8 percent of control) (p

Precision assessment and radiation safety for dual-energy X-ray absorptiometry: position paper of the International Society for Clinical Densitometry.

Measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) is used to diagnose osteoporosis, assess the risk of fracture, and monitor changes in BMD over time. Because biological changes in BMD are usually small in proportion to the error inherent in the test itself, interpretation of serial BMD tests depends on knowledge of the smallest change in BMD that is beyond the range of error. This value, called the least significant change (LSC), varies according to the instrument used, the patient population being tested, the measurement site, the skill of the technologist at positioning the patient and analyzing the test, and the confidence interval used in the calculation. The precision and LSC values provided by the manufacturer cannot be applied to clinical bone densitometry centers because of the differences in the patients being tested and the technologist performing the test. Because harmful errors in clinical management may occur from incorrectly interpreting serial BMD tests, it is recommended that every DXA technologist conduct a precision assessment and calculate the LSC for each measurement site and DXA instrument used. Precision assessment provides direct benefit to patients by allowing clinicians to make clinical decisions based on genuine change or stability of BMD. The patient-care benefits of precision assessment outweigh the risk of exposure to trivial doses of ionizing radiation.

Deficient activity of guanine nucleotide regulatory protein in erythrocytes from patients with pseudohypoparathyroidism

Abstract The activity in two assay systems of guanine nucleotide regulatory protein was significantly lower in red cells from pseudohypoparathyroid patients compared to that of normal subjects. The results support the hypothesis that deficient activity of the guanine nucleotide regulatory protein is the molecular basis for hormone resistance in this inherited disorder.

Urinary calcium excretion in familial hypocalciuric hypercalcemia. Persistence of relative hypocalciuria after induction of hypoparathyroidism

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant trait comprising hypercalcemia, hypophosphatemia, parathyroid hyperplasia, and unusually low renal clearance of calcium. We evaluated the role of parathyroid hormone in the relative hypocalciuria of FHH and characterized the renal transport of calcium in this disorder using three previously hypercalcemic FHH patients with surgical hypoparathyroidism and three controls with surgical hypoparathyroidism. Intravenous infusion of calcium chloride in two patients with FHH and in three controls increased serum calcium from a mean basal of 5.0 to a mean peak of 6.8 meq/liter in two FHH patients and from 4.2 to 5.7 in three control subjects. Urinary calcium in a third FHH patient was studied without calcium infusion during recovery from hypercalcemia of vitamin D intoxication. At all serum concentrations of calcium, calcium clearance was lower in FHH than in controls; at base-line serum calcium, the ratio of calcium clearance to inulin clearance (C(Ca)/C(IN)) in FHH subjects was 32% of that in controls and decreased to 19% during hypercalcemia. Calcium infusion increased the ratio of sodium clearance to inulin clearance in controls from a base line of 0.020 to 0.053 at peak concentrations of calcium in serum, but did not affect this parameter in FHH (0.017 at base-line serum calcium vs. 0.019 at peak). When calcium infusion studies were performed (in two patients with FHH and one control) during administration of acetazolamide, a drug whose principal renal action causes inhibition of proximal transport of solute, C(Ca)/C(IN) in the patients with FHH was 29 and 7% of that of the control at base-line and peak serum calcium, respectively. In contrast, ethacrynic acid, a diuretic that acts in the ascending limb of the loop of Henle, increased C(Ca)/C(IN) more in the FHH patients than in the control subject; C(Ca)/C(IN) was 65% at base-line and 47% at peak serum calcium, compared with that of the control subject. The greater calciuric response to ethacrynic acid than to acetazolamide or calcium infusion alone in FHH indicates that a major renal locus of abnormal calcium transport in this disorder may be the ascending limb of the loop of Henle.Decreased clearance of calcium in patients with FHH and hypoparathyroidism when compared with hypoparathyroid controls indicates that relative hypocalciuria in FHH is not dependent on hyperparathyroidism. Since the parathyroid glands in FHH are not appropriately suppressed by calcium, this implies that FHH represents a disorder of abnormal transport of, and/or response to, extracellular calcium in at least two organs, parathyroid gland and kidney.

Effect of raloxifene on the risk of new vertebral fracture in postmenopausal women with osteopenia or osteoporosis : a reanalysis of the Multiple Outcomes of Raloxifene Evaluation trial

Raloxifene reduces vertebral fracture risk in postmenopausal women with osteoporosis and established osteoporosis, but its efficacy in women with osteopenia has not been studied. The objective of this study was to evaluate the effect of raloxifene hydrochloride on the risk of vertebral fractures in postmenopausal women with osteopenia and to compare this effect with that in women with osteoporosis as defined by the bone mineral density (BMD) T-score at the hip. We studied the 3204 postmenopausal women with osteopenia or osteoporosis without vertebral fractures at baseline in the Multiple Outcomes of Raloxifene Evaluation trial. Compared with placebo, 60 mg/day raloxifene reduced the risk of new vertebral fractures at 3 years independent of baseline total hip BMD. The relative risk for new vertebral fractures for the raloxifene group compared with placebo was 0.53 (95% CI, 0.32-0.88) for those with osteopenia and 0.31 (0.06-0.71) for those with osteoporosis. In raloxifene-treated women the rate of vertebral fracture was similar in women with osteoporosis (2%) to that in women with osteopenia (1.9%). For clinically apparent vertebral fractures, the relative risk of fracture in the osteopenia group for raloxifene was 0.25 (0.04-0.63) compared with placebo. There were no new clinical vertebral fractures in women with osteoporosis receiving raloxifene, whereas four occurred in the placebo group. We conclude that treatment with 60 mg/day raloxifene significantly decreases the risk of new vertebral fractures and new clinical vertebral fractures in postmenopausal women without baseline vertebral fracture who have osteopenia or osteoporosis.

Clinical implications of guanine nucleotide-binding proteins as receptor-effector couplers.

IT has long been known that some cellular proteins bind guanine nucleotides such as guanosine tri-phosphate (GTP) with high affinity. These binding proteins are called G proteins and have been link...

Familial Hypocalciuric Hypercalcemia: Recognition Among Patients Referred After Unsuccessful Parathyroid Exploration

Of 67 patients referred after unsuccessful surgery for presumed primary hyperparathyroidism, six were shown to be members of kindreds with familial hypocalciuric hypercalcemia. This diagnosis had not been recognized in any of the six previosuly. Most of the remaining 61 cases had proven or probable typical primary hyperparathyroidism, and a subgroup of four had hypercalcemia with suppression of the parathyroid glands. Urine calcium excretion expressed as the calcium:creatinine clearance ratio provided an easily measurable and effective index to separate the groups with familial hypocalciuric hypercalcemia, typical primary hyperparathyroidism, and suppressed parathyroids. Thus, at least 9% of patients referred after unsuccessful parathyroidectomy had familial hypocalciuric hypercalcemia. The assessment of urine calcium excretion by indices such as the calcium:creatinine clearance ratio should facilitate recognition of this condition, which responds poorly to standard subtotal parathyroidectomy.

Vanadate stimulates adenylate cyclase via the guanine nucleotide regulatory protein by a mechanism differing from that of fluoride

Vanadate stimulates adenylate cyclase activity in turkey erythrocyte membranes. The maximal stimulation is 7-fold over basal at 3 mM vanadate; higher concentrations are inhibitory. A suboptimal concentration of fluoride (1 mM) together with vanadate (3 mM) activates adenylate cyclase in a non-additive manner; cyclase activation by optimal fluoride (10 mM) is inhibited by vanadate (3 mM). There is no stimulation by vanadate of adenylate cyclase activity (measured either with Mg2+ or Mn2+) in CYC- S49 lymphoma cell membranes. Vanadate (3 mM) shows no effect on binding of Beta-adrenergic agonists or antagonists to the [3H] (-)-dihydroalprenolol binding site in turkey erythrocyte membranes. These results suggest that the effect of vanadate on Adenylate cyclase is mediated through the nucleotide regulatory protein and may act by a mechanism similar to fluoride. However, in cholera toxic-treated membranes as well as in GDP-beta-S plus isoproterenol-treated membranes, fluoride-stimulated adenylate cyclase activity is significantly reduced, but vanadate stimulation is not. Our results suggest that although the actions of vanadate and fluoride in adenylate cyclase may each involve the nucleotide regulatory unit, the exact mechanisms of activation by the two anions differ.

Persistence and switching patterns among women with varied osteoporosis medication histories: 12-month results from POSSIBLE US™

SummaryDuring the first year of Prospective Observational Scientific Study Investigating Bone Loss Experience (POSSIBE US™), many women transitioned (i.e., discontinued or switched) from their baseline osteoporosis medication. Participants not on stable therapy at entry, with side effects, and with poor physical status were at higher risk of transitioning. Understanding factors associated with persistence may lead to improved outcomes.IntroductionPostmenopausal osteoporosis (PMO) medication use patterns may differ by treatment history and drug class. We describe these patterns among patients in primary care settings using patient-reported data.MethodsData from 3,006 participants of the POSSIBLE US™ were used to estimate the probability of a baseline PMO medication transition (i.e., discontinuation or switch) and hazard ratios (HRs) for predictors of these transitions.ResultsOne year after study entry, the probability of persisting with a baseline medication was 66% (95% CI: 64–68%). After adjusting for age and osteoporosis diagnosis, factors at entry independently associated with a higher risk of baseline medication transition were treatment status cohort, side effect severity, and OPAQ-SV physical function score. Compared to participants stable on therapy at entry, others had a higher risk, ranging from HR = 1.59 (95% CI: 1.36–1.85) for those new to therapy to HR = 2.00 (95% CI: 1.27–3.15) for those who recently augmented therapy at entry. Participants reporting moderate (HR = 1.31, 95% CI: 1.09–1.57) or severe (HR = 1.88, 95% CI: 1.49–2.39) side effects had a higher risk than those not reporting side effects. Participants reporting Osteoporosis Assessment Questionnaire-Short Version physical function scores in the lowest tertile had a higher risk (HR = 1.27, 95% CI: 1.07–1.52) than those reporting scores in the highest tertile.ConclusionBaseline osteoporosis medication transitions were common in the first year of POSSIBLE US™. Participants not on stable therapy at entry, or who reported severe side effects, or had poor physical health status were at higher risk for these transitions.