Ove Tørring

Treatment with Denosumab Reduces the Incidence of New Vertebral and Hip Fractures in Postmenopausal Women at High Risk

CONTEXT The FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) trial showed denosumab significantly reduced the risk of fractures in postmenopausal women with osteoporosis. OBJECTIVE We evaluated the effect of denosumab on the incidence of new vertebral and hip fractures in subgroups of women at higher risk for these fractures. DESIGN FREEDOM was a 3-yr, randomized, double-blind, placebo-controlled, phase 3 trial. PARTICIPANTS AND SETTING Postmenopausal women (N = 7808) with osteoporosis were enrolled at 213 study sites worldwide. INTERVENTIONS Subjects received s.c. denosumab (60 mg) or placebo every 6 months and daily supplements of calcium (≥1000 mg) and vitamin D (≥400 IU). MAIN OUTCOME MEASURES This post hoc analysis evaluated fracture incidence in women with known risk factors for fractures including multiple and/or moderate or severe prevalent vertebral fractures, aged 75 yr or older, and/or femoral neck bone mineral density T-score of -2.5 or less. RESULTS Compared with placebo, denosumab significantly reduced the risk of new vertebral fractures in women with multiple and/or severe prevalent vertebral fractures (16.6% placebo vs. 7.5% denosumab; P < 0.001). Similarly, denosumab significantly reduced the risk of hip fractures in subjects aged 75 yr or older (2.3% placebo vs. 0.9% denosumab; P < 0.01) or with a baseline femoral neck bone mineral density T-score of -2.5 or less (2.8% placebo vs. 1.4% denosumab; P = 0.02). These risk reductions in higher-risk individuals were consistent with those seen in patients at lower risk of fracture. CONCLUSIONS Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at higher risk for fracture. These results highlight the consistent antifracture efficacy of denosumab in patients with varying degrees of fracture risk.

Biochemical hyperparathyroidism and bone mineral status in patients treated long-term with lithium

Lithium is known to interfere with normal calcium homeostasis, but the long-term effects and possible clinical significance are uncertain. Thus, we measured indices of parathyroid function including intact parathyroid hormone (PTH) and ionized and total calcium levels in 26 patients treated for manic-depressive psychosis with lithium for 10 years or longer (mean +/- SD duration, 15 +/- 6 years). Increased ionized calcium levels were found in 11 patients and increased PTH concentrations in five patients. Altogether, 54% of the patients (14 of 26) had ionized calcium and/or PTH levels above the laboratory reference range. The PTH/ionized calcium relationship of the lithium-treated patients was compared with that of a group of normal subjects (n = 23) and with those of three different groups of patients with abnormal parathyroid function (chronic hypoparathyroidism, n = 21; primary hyperparathyroidism [HPT], n = 50; and tertiary HPT, n = 21). Lithium-treated patients had significantly higher ionized calcium levels (P < .0001) but not significantly higher PTH concentrations (P = .08) than the normal subjects. In comparison to the normal controls, lithium-treated patients had a right-sided shift in their PTH/ionized calcium relationship that was in the same direction but less prominent than in primary or tertiary HPT. Dual-energy x-ray absorptiometry disclosed similar bone mineral densities (BMDs) of lithium-treated patients and age-, sex-, and body mass-matched normal controls in the whole body, lumbar spine, and femoral neck (Z scores: +1.20, +1.22, and +1.02, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Discontinuation of denosumab and associated fracture incidence: Analysis from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Trial

Osteoporosis is a chronic disease and requires long‐term treatment with pharmacologic therapy to ensure sustained antifracture benefit. Denosumab reduced the risk for new vertebral, nonvertebral, and hip fractures over 36 months in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. Whereas discontinuation of denosumab has been associated with transient increases in bone remodeling and declines in bone mineral density (BMD), the effect on fracture risk during treatment cessation is not as well characterized. To understand the fracture incidence between treatment groups after cessation of investigational product, we evaluated subjects in FREEDOM who discontinued treatment after receiving two to five doses of denosumab or placebo, and continued study participation for ≥7 months. The off‐treatment observation period for each individual subject began 7 months after the last dose and lasted until the end of the study. This subgroup of 797 subjects (470 placebo, 327 denosumab), who were evaluable during the off‐treatment period, showed similar baseline characteristics for age, prevalent fracture, and lumbar spine and total hip BMD T‐scores. During treatment, more placebo‐treated subjects as compared with denosumab‐treated subjects sustained a fracture and had significant decreases in BMD. During the off‐treatment period (median 0.8 years per subject), 42% versus 28% of placebo‐ and denosumab‐treated subjects, respectively, initiated other therapy. Following discontinuation, similar percentages of subjects in both groups sustained a new fracture (9% placebo, 7% denosumab), resulting in a fracture rate per 100 subject‐years of 13.5 for placebo and 9.7 for denosumab (hazard ratio [HR] 0.82; 95% confidence interval [CI], 0.49–1.38), adjusted for age and total hip BMD T‐score at baseline. There was no apparent difference in fracture occurrence pattern between the groups during the off‐treatment period. In summary, there does not appear to be an excess in fracture risk after treatment cessation with denosumab compared with placebo during the off‐treatment period for up to 24 months.

Effect of acute endurance and strength exercise on circulating calcium‐regulating hormones and bone markers in young healthy males

Physical activity plays a role in the maintenance of the skeleton but the mechanical, metabolic and hormonal mechanisms involved are largely unknown. The influnence of acute endurance and strength exercise on circulating levels of calcitonin, parathyroid hormone (PTH), PTH‐related peptide (PTHrP), osteocalcin, carboxyterminal cross‐linked telopeptide of type I collagen (ICTP) and ionized calcium (Ca2+) was therefore evaluated. Eight healthy young males performed three exercise bouts on separate accasions: endurance exercise i.e. cycling on a cycle ergometer for 45 mim at 55% of Vo2max (E55%) and 15 min at 85% of Vo2max (E 85%) and strength exercise at 85% of three repetitions maximum using a legpress device (STR). Control experiments included the same subjects with the same time schedule but without exercise. Blood samples were taken before, immediately after exercise and during the recovery period. Hormones and bone markers were measured by use of various immunoassays. There was no obvious influence on calcitonin and PTHrP levels, whereas PTH was increased after strength exercise. ICTP and osteocalcin levels correlated positively at all times and showed regular variations. In comparison with the controls, ICTP levels showed a more pronounced decrease following physical activity whereas osteocalcin followed the same pattern as the controls except for after prolonged endurance exercise when a decrease was abolished. In conclusion, an increase in PTH after strength exercise and a pronounced decrease in ICTP after all exercise together with a relative increase in osteocalcin after prolonged endurance exercise might reflect some mechanisms involved in the positive effect of physical activity on bone mass.

Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension

Denosumab reduces bone resorption and vertebral and nonvertebral fracture risk. Denosumab discontinuation increases bone turnover markers 3 months after a scheduled dose is omitted, reaching above‐baseline levels by 6 months, and decreases bone mineral density (BMD) to baseline levels by 12 months. We analyzed the risk of new or worsening vertebral fractures, especially multiple vertebral fractures, in participants who discontinued denosumab during the FREEDOM study or its Extension. Participants received ≥2 doses of denosumab or placebo Q6M, discontinued treatment, and stayed in the study ≥7 months after the last dose. Of 1001 participants who discontinued denosumab during FREEDOM or Extension, the vertebral fracture rate increased from 1.2 per 100 participant‐years during the on‐treatment period to 7.1, similar to participants who received and then discontinued placebo (n = 470; 8.5 per 100 participant‐years). Among participants with ≥1 off‐treatment vertebral fracture, the proportion with multiple (>1) was larger among those who discontinued denosumab (60.7%) than placebo (38.7%; p = 0.049), corresponding to a 3.4% and 2.2% risk of multiple vertebral fractures, respectively. The odds (95% confidence interval) of developing multiple vertebral fractures after stopping denosumab were 3.9 (2.1–7. 2) times higher in those with prior vertebral fractures, sustained before or during treatment, than those without, and 1.6 (1.3–1.9) times higher with each additional year of off‐treatment follow‐up; among participants with available off‐treatment total hip (TH) BMD measurements, the odds were 1.2 (1.1–1.3) times higher per 1% annualized TH BMD loss. The rates (per 100 participant‐years) of nonvertebral fractures during the off‐treatment period were similar (2.8, denosumab; 3.8, placebo). The vertebral fracture rate increased upon denosumab discontinuation to the level observed in untreated participants. A majority of participants who sustained a vertebral fracture after discontinuing denosumab had multiple vertebral fractures, with greatest risk in participants with a prior vertebral fracture. Therefore, patients who discontinue denosumab should rapidly transition to an alternative antiresorptive treatment. Clinicaltrails.gov: NCT00089791 (FREEDOM) and NCT00523341 (Extension).

Sodium and potassium disturbances in the elderly: Prevalence and association with drug use

ObjectiveTo study the incidence of sodium and potassium disturbances in a population of the very old elderly, with respect to medication with potential effects on electrolyte levels.Design and settingCross-sectional study of subjects aged ≥75 years, based on data from the Kungsholmen project, a population-based study of elderly in an urban area of Stockholm, Sweden.Study participants1558 elderly individuals (1178 women and 380 men), mean age 81.4 years, providing information about drug use and serum electrolyte data.Main outcome measuresData on drug use was based on personal interviews. Hyponatraemia was defined as a serum sodium concentration <136 mmol/L, hypernatraemia as a serum sodium concentration >146 mmol/L, hypokalaemia as a serum potassium concentration <3.5 mmol/L and hyperkalaemia as a serum potassium concentration >5.0 mmol/L.ResultsHyponatraemia was found in 147 subjects (9.4% of the study population) and hypernatraemia in five individuals (0.3%). Hypokalaemia was found in 39 (2.5%) and hyperkalaemia in 43 (2.8%) of the subjects. The prevalence of hyponatraemia (p < 0.001), hypokalaemia (p < 0.05) and hyperkalaemia (p < 0.05) increased with age. Hyponatraemia was found more often in women than in men (p < 0.05). Hypernatraemia was more frequent in subjects who lived in institutions (p < 0.001). The occurrence of hyponatraemia was associated with the use of carbamazepine, laxatives (enema), diuretics and ACE-inhibitors; hypernatraemia was associated with osmotically active laxatives. Hypokalaemia was associated with thiazide-related and combination diuretics; and hyperkalaemia was associated with potassium-sparing diuretics, β-blockers, cytostatic drugs and tricyclic antidepressants.ConclusionsThe present study demonstrated the association between electrolyte level disturbances and several types of drugs in a population of the very old elderly. Our results underline the importance of monitoring serum electrolyte levels in the elderly, not only in relation to the use of diuretics, but also several other drugs.

Parathyroid hormone-related peptide in human milk measured by a mid-molecule radioimmunoassay

Several peptide hormones and growth factors have been found in human milk, and we present here the results of measurements of parathyroid hormone-related peptide (PTHrP). A radioimmunoassay (RIA) using a polyclonal antiserum against the mid-region of the molecule has been developed. In milk collected during the first 6 days after parturition, the PTHrP concentrations showed large interindividual variations ranging from 0.3 to 13.7 nmol-Eq/L (0.5 to 24.4 ng-Eq/mL) (n = 67) and increased between days 3 and five postpartum. PTHrP also increased during the first 4 collecting days when measured in milk from the same mother during a prolonged period. On fast-protein liquid chromatography (FPLC), the bulk of PTHrP eluted with a molecular weight of approximately 10 to 12 kd after treatment with urea. After mid-molecule immunoaffinity extraction of PTHrP from milk, higher levels were obtained by the mid-molecule RIA than by an aminoterminal assay, indicating that all fragments did not contain the aminoterminal. Parts of immunoextracted milk PTHrP stimulated cyclic adenosine monophosphate (cAMP) production in rat osteosarcoma cell line, UMR-106. In conclusion, we have found PTHrP-like immunoreactivity in human milk using a mid-region RIA. Parts of the immunoextracts also contained the aminoterminal and possessed PTH-like bioactivity. Whether PTHrP in human milk plays a physiological role in the maternal breast or in the newborn gastrointestinal tract is unknown, but the present observations demonstrate that a portion of the PTHrP is at least potentially biologically active.

Osteonecrosis of the jaw in Sweden associated with the oral use of bisphosphonate.

PURPOSE To estimate the incidence of bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) associated with the use of oral BPs and osteonecrosis of the jaw (ONJ) not associated with current or previous medication with a BP or radiotherapy to the head and neck region (background ONJ) in Sweden. MATERIALS AND METHODS A survey was sent to all oral and maxillofacial surgery clinics and hospital dental clinics in Sweden. They were requested to report all new cases of BRONJ and background ONJ during 2007 and 2008. RESULTS The response rate was 61%. The oral BRONJ incidence for patients aged 45 years or older was 67 cases/100,000 patient-years of BP medication in 2007 (1 case/1,500 patient-years). In 2008, 69 cases/100,000 patient-years (1 case/1,445 patient-years) were reported. The mean age at the development of oral BRONJ was 76.5 ± 10.8 years (median age 79, range 49 to 96) for 2007 and 79.8 ± 7.6 years (median 79, range 67 to 94) for 2008. Women were primarily affected (22 of 26 in 2007 and 25 of 29 in 2008). The incidence of background ONJ was low: 0.14 and 0.09/100,000 person-years for those aged 45 years or older in 2007 and 2008, respectively (3 cases in 2007 and 2 in 2008). CONCLUSIONS The BRONJ incidence has been estimated to be more than 100-fold greater than the incidence of background ONJ. However, an average Swedish dental practice (1,234 patients) will only encounter 1 patient with new oral BRONJ every 62 nd year.

Salmon calcitonin treatment by nasal spray in primary hyperparathyroidism

The hypocalcemic and hypophosphatemic effect of salmon calcitonin (sCT) given by intranasal (i.n.) spray to 12 patients with histological confirmed primary hyperparathyroidism (1 degree HPT) was studied. The concentration of ionized calcium in whole blood (B-Ca++), serum phosphate (S-P), magnesium (S-Mg), plasma sCT (Pl-sCT), and endogenous CT (hCT) was followed during five 24-hour periods with at least three days between. After period I (control day), 100 IU sCT was given intramuscularly (i.m.) in period II. In periods III-V, either 110, 200, or 400 IU of sCT were given intranasally (i.n.) in randomized order. Although B-Ca++ decreased from the baseline value with all four sCT treatments and at 4.5 hour on the control day (p less than 0.05-0.001), the i.n. sCT treatments had no significant hypocalcemic effect, as the change of the area under the B-Ca++ curve (delta AUC B-Ca++) for the three i.n. treatments was not significantly different from the control period (p less than 0.001, ANOVA). Only the i.m. injection of calcitonin had a calcium-lowering effect (p less than 0.001, ANOVA). Three subjects were considered nonresponders with a decrease in B-Ca++ less than 0.06 mmol/L. S-P decreased within three hours after 200 IU sCT i.n. and 100 IU i.m., but the S-Mg levels showed no consistent changes. The area under the curve for the Pl-sCT levels did not correlate with delta AUC B-Ca++ except for i.m. given sCT.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of denosumab on bone density, mass and strength in women with postmenopausal osteoporosis

Denosumab is a human monoclonal antibody which specifically blocks receptor activator of nuclear factor κB ligand and is a very potent antiresorptive drug. Its efficacy in reducing the risk of vertebral, hip and nonskeletal fracture has been proven in a large prospective, randomized multicenter study of 7808 postmenopausal women with osteoporosis [Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial]. Denosumab causes somewhat greater increases in bone mineral density (BMD) than the class of bisphosphonate antiresorptives. Denosumab also causes an increase in bone mass and bone strength in the spine, ultradistal and diaphysis of the radius, proximal tibia and the hip. Recently long-term treatment with denosumab has been shown to cause a continued almost linear increase in total hip and femoral neck BMD beyond 3 years up to 8 years. In this respect, denosumab seems to differ from the bisphosphonate group in which the rate of improvement of BMD diminishes and for some drugs becomes negative after 3–4 years when the process of secondary mineralization flattens out. This unique property of an antiresorptive drug points towards mechanisms of action which differ from the bisphosphonate group. Both types of antiresorptives decrease cortical porosity but contrary to bisphosphonates the reduction in cortical porosity continues with denosumab which, in addition, also seems to cause a slight continuous modeling-based formation of new bone despite suppression of bone remodeling. The net effect is an increase in cortical thickening and bone mass, and increased strength of cortical bone. This may contribute substantially to the significant further reduction of the nonvertebral fracture risk which was found in the long-term denosumab arm of the FREEDOM extension trial during years 4–7.Denosumab is a human monoclonal antibody which specifically blocks receptor activator of nuclear factor κB ligand and is a very potent antiresorptive drug. Its efficacy in reducing the risk of vertebral, hip and nonskeletal fracture has been proven in a large prospective, randomized multicenter study of 7808 postmenopausal women with osteoporosis [Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial]. Denosumab causes somewhat greater increases in bone mineral density (BMD) than the class of bisphosphonate antiresorptives. Denosumab also causes an increase in bone mass and bone strength in the spine, ultradistal and diaphysis of the radius, proximal tibia and the hip. Recently long-term treatment with denosumab has been shown to cause a continued almost linear increase in total hip and femoral neck BMD beyond 3 years up to 8 years. In this respect, denosumab seems to differ from the bisphosphonate group in which the rate of improvement of BMD diminishes and for some drugs becomes negative after 3–4 years when the process of secondary mineralization flattens out. This unique property of an antiresorptive drug points towards mechanisms of action which differ from the bisphosphonate group. Both types of antiresorptives decrease cortical porosity but contrary to bisphosphonates the reduction in cortical porosity continues with denosumab which, in addition, also seems to cause a slight continuous modeling-based formation of new bone despite suppression of bone remodeling. The net effect is an increase in cortical thickening and bone mass, and increased strength of cortical bone. This may contribute substantially to the significant further reduction of the nonvertebral fracture risk which was found in the long-term denosumab arm of the FREEDOM extension trial during years 4–7.