The Summary To test the hypothesis that during treatment with denosumab osteomorphs and precursors recycle to higher number of osteoclasts with time, we measured TRAcP5b in serum taken 6 months... Show moreThe Summary To test the hypothesis that during treatment with denosumab osteomorphs and precursors recycle to higher number of osteoclasts with time, we measured TRAcP5b in serum taken 6 months after the last injection in postmenopausal women treated for 1-10 years. Serum TRAcP5b values were not related to time of exposure to denosumab.Purpose In women with postmenopausal osteoporosis the aetiology of the observed inverse relationship between duration of denosumab (Dmab) therapy and bone loss after its discontinuation is currently unknown. In studies in mice inhibition of RANKL is associated with an increase in osteomorphs and osteoclast precursors that recycle into osteoclasts and may accumulate with time. We hypothesized that longer inhibition of RANKL by Dmab will be followed by the synchronous formation of a larger number of osteoclasts after stopping treatment. To test this hypothesis, we measured serum TRAcP5b, a marker of osteoclast numbers, in postmenopausal women treated with Dmab for different periods of time up to 10 years.Methods TRAcP5b, C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at 6.0 months +/- 15 days after last Dmab injection in 59 women who had received Dmab for 4.0 +/- 2.3 years (range 1-10 years). Of these, 38 were treatment naive (group 1) and 21 had received other treatments prior Dmab (group 2).Results Duration of Dmab treatment was not related to serum TRAcP5b values or to TRAcP5b/CTX ratio either in the whole cohort or in each of the two groups separately. In contrast, serum TRAcP5b values were significantly correlated with serum CTX values (r(s) = 0.619; p < 0.001), but not with serum P1NP values or BMD at all skeletal sites.Conclusion Our observations indicate that serum TRAcP5b, measured at 6 months after a Dmab injection, is not a useful early marker for time-dependent increased accumulation of osteoclasts in humans and for identification of patients at risk for a higher rebound increase in bone resorption. Show less
The long-term effects of zoledronate treatment in women with postmenopausal osteoporosis who stop denosumab therapy when they become osteopenic are not known. In a prospective, randomized,... Show moreThe long-term effects of zoledronate treatment in women with postmenopausal osteoporosis who stop denosumab therapy when they become osteopenic are not known. In a prospective, randomized, controlled clinical trial we previously reported that a single intravenous infusion of zoledronate 5 mg given to such patients 6 months after the last denosumab injection effectively prevents bone loss in the majority of them for up to 3 years. The study was extended for an additional 2 years and included all 19 patients from one Trial Site of the total 27 patients originally randomized in the zoledronate arm. Baseline characteristics of this cohort treated with denosumab for 2.4 & PLUSMN; 0.2 years were not different from those of the whole initial cohort or from the patients who did not participate in this extension. At the end of 5 years 7 patients had become again osteoporotic requiring additional treatment, 9 remained osteopenic while 3 did not complete the study extension. Thus, more than half of the osteoporotic women who became osteopenic with denosumab treatment and stopped it, maintained the BMD gains 5 years after a single zoledronate infusion with no additional treatment. Whether these results are also applicable to patients treated with denosumab for longer periods remains to be established. Show less
Schoeb, M.; Winter, E.M.; Malgo, F.; Schipper, I.B.; Wal, R.J.P. van der; Papapoulos, S.E.; Appelman-Dijkstra, N.M. 2022
Bone material properties were assessed using impact microindentation in patients with high-energy trauma fractures. Compared to patients with low-energy trauma fractures, bone material strength... Show moreBone material properties were assessed using impact microindentation in patients with high-energy trauma fractures. Compared to patients with low-energy trauma fractures, bone material strength index was significantly higher in patients with high-energy trauma fractures, and did not differ between patients with osteopenia and those with osteoporosis within each trauma group. Introduction Impact microindentation (IMI) is a technique to assess tissue-level properties of bone at the tibia. Bone material strength index (BMSi), measured by IMI, is decreased in patients with low-energy trauma fractures, independently of areal bone mineral density (aBMD), but there is no information about BMSi in patients with high-energy trauma fractures. In the present study, we evaluated tissue-level properties of bone with IMI in patients with high-energy trauma fractures. Methods BMSi was measured 3.0 months (IQR 2.0-5.8) after the fracture in 40 patients with high-energy trauma and 40 age- and gender-matched controls with low-energy trauma fractures using the OsteoProbe (R) device. Results Mean age of high- and low-energy trauma patients was 57.7 +/- 9.1 and 57.2 +/- 7.7 years, respectively (p = 0.78). Fracture types were comparable in high- vs low-energy trauma patients. Lumbar spine (LS)-aBMD, but not femoral neck (FN)-aBMD, was higher in high- than in low-energy trauma patients (LS 0.96 +/- 0.13 vs 0.89 +/- 0.13 g/cm(2), p = 0.02; FN 0.75 +/- 0.09 vs 0.72 +/- 0.09 g/cm(2), p = 0.09). BMSi was significantly higher in high- than in low-energy trauma patients (84.4 +/- 5.0 vs 78.0 +/- 4.6, p = 0.001), also after adjusting for aBMD (p = 0.003). In addition, BMSi did not differ between patients with osteopenia and those with osteoporosis within each trauma group. Conclusion Our data demonstrate that BMSi and LS-aBMD, but not FN-aBMD, are significantly higher in high-energy trauma patients compared to matched controls with similar fractures from low-energy trauma. Further studies of non-osteoporotic patients with high-energy trauma fracture with measurements of BMSi are warranted to determine whether IMI might help in identifying those with reduced bone strength. Show less
Makras, P.; Appelman-Dijkstra, N.M.; Papapoulos, S.E.; Wissen, S. van; Winter, E.M.; Polyzos, S.A.; ... ; Anastasilakis, A.D. 2021
Context: Zoledronate is used to prevent bone loss following denosumab discontinuation but its efficacy differs among studies.Objective: To test if the duration of denosumab treatment affects the... Show moreContext: Zoledronate is used to prevent bone loss following denosumab discontinuation but its efficacy differs among studies.Objective: To test if the duration of denosumab treatment affects the efficacy of subsequent zoledronate infusion.Methods: This multicenter, prospective cohort study, conducted at 2 Greek and 1 Dutch bone centers, included 47 postmenopausal women (n=47) who received a single zoledronate infusion 6 months after the last denosumab injection and then were followed for 1 year. Twenty-seven women received <= 6 denosumab injections (<= 6 Group) and 20 received>6 denosumab injections (> 6 Group). The main outcome measure was changes in lumbar spine (LS) bone mineral density (BMD).Results: At 12 months LS-BMD values were maintained in the <= 6 Group (0.980.10 to 0.99 +/- 0.9 g/cm(2), P=0.409) but decreased significantly in the>6 Group (1.0 +/- 0.11 to 0.93 +/- 0.12 g/cm(2), P<0.001). The percent change of LS-BMD of the <= 6 Group (+1.0%) was significantly different (P<0.001) from the change of the>6 Group (-7.0%). In the whole cohort, the duration of denosumab treatment was negatively correlated with the percentage change of LS-BMD (r(s) = -0.669, P<0.001) but not with the change of femoral neck (FN)-BMD. Bone turnover markers increased in all patients 6 months following zoledronate administration with no difference between the 2 groups.Conclusion: The duration of denosumab treatment significantly affects the efficacy of subsequent zoledronate infusion to maintain BMD gains. Frequent follow-up of patients treated with denosumab longer than 3 years is advisable as additional therapeutic interventions may be needed. Show less
Primary osteoporosis is rare in children and adolescents and its optimal pharmacological management is uncertain. Bisphosphonates are commonly used while denosumab has only been administered to a... Show morePrimary osteoporosis is rare in children and adolescents and its optimal pharmacological management is uncertain. Bisphosphonates are commonly used while denosumab has only been administered to a few children with osteogenesis imperfecta. We studied a treatment-naive 13.5-year-old boy with severe osteoporosis and multiple vertebral deformities who presented with back pain and difficulty in walking. Causes of secondary osteoporosis were excluded and there were no abnormalities in genes known to cause bone fragility. He was treated with denosumab 60 mg subcutaneously every 3 months for 30 months, and he was pain-free within 6 weeks after the first injection. Lumbar spine BMD and femoral neck BMD increased with treatment by 65.6% and 25.3%, respectively, and deformed vertebrae regained their normal shape; linear growth was not impaired. During the second year of treatment, transient hypercalcemia (maximum 3.09 mmol/l) before the denosumab injection was observed. In conclusion, denosumab was highly effective in this case of primary pediatric osteoporosis, with remarkable clinical and radiological response. Transient hypercalcemia was probably due to amplification of the effect of growth spurt and puberty on bone remodeling by the transient, short-term discontinuation of the drug. Furthermore, our data suggest that mobilization of calcium from treatment-induced sclerotic transverse lines in bone metaphyses may contribute to the development of hypercalcemia. Show less
Pycnodysostosis, a rare autosomal recessive skeletal dysplasia, is caused by a deficiency of cathepsin K. Patients have impaired bone resorption in the presence of normal or increased numbers of... Show morePycnodysostosis, a rare autosomal recessive skeletal dysplasia, is caused by a deficiency of cathepsin K. Patients have impaired bone resorption in the presence of normal or increased numbers of multinucleated, but dysfunctional, osteoclasts. Cathepsin K degrades collagen type I and generates N-telopeptide (NTX) and the C-telopeptide (CTX) that can be quantified. Levels of these telopeptides are increased in lactating women and are associated with increased bone resorption. Nothing is known about the consequences of cathepsin K deficiency in lactating women. Here we present for the first time normalized blood and CTX measurements in a patient with pycnodysostosis, exclusively related to the lactation period. In vitro studies using osteoclasts derived from blood monocytes during lactation and after weaning further show consistent bone resorption before and after lactation. Increased expression of cathepsins L and S in osteoclasts derived from the lactating patient suggests that other proteinases could compensate for the lack of cathepsin K during the lactation period of pycnodysostosis patients. Show less
Introduction: In women with postmenopausal osteoporosis denosumab discontinuation is associated with rapid bone loss that could be potentially prevented by a single zoledronate infusion for two... Show moreIntroduction: In women with postmenopausal osteoporosis denosumab discontinuation is associated with rapid bone loss that could be potentially prevented by a single zoledronate infusion for two years. The longer-term effects, however, of zoledronate treatment are unknown. We aimed to study the effect of a single zoledronate infusion during the third year following denosumab discontinuation, in initially treatment-naive postmenopausal women who became osteopenic after 2.4 +/- 0.2 years of denosumab therapy.Methods: We report the 1-year follow-up results of a single arm observational extension of a previously reported 2-year multicenter prospective randomized clinical trial. The primary endpoint of this extension was the change in lumbar spine bone mineral density (LS-BMD); secondary endpoints were changes in femoral neck (FN)-BMD and markers of bone turnover (BTM) during the 3rd year from the zoledronate infusion. Changes are presented as mean and SEM.Results: LS-BMD did not change significantly at year 3 compared to year 2 (-1.35 +/- 1.1%, p = 1.00) and compared to baseline ( -1.96 +/- 1.44%, p = 1.00). FN-BMD values did not change while serum P1NP values decreased and CTX values remained unchanged during the third-year of the follow-up. In 4 of the 23 studied women BMD values returned to the osteoporotic range at 3 years.Conclusions: A single i.v. infusion of zoledronate 5 mg, given 6 months after the last injection of denosumab therapy maintains for three years BMD gains in the majority of patients previously treated with denosumab for an approximate period of 2.5 years. Follow-up of patients is, however, recommended because about one-fifth of treated women will require additional antiosteoporotic treatment. Show less
Acute phase response (APR) following intravenous zoledronate (ZOL) administration is related to activation and increased proliferation of gamma delta T cells, attributed to the molecular mechanism... Show moreAcute phase response (APR) following intravenous zoledronate (ZOL) administration is related to activation and increased proliferation of gamma delta T cells, attributed to the molecular mechanism of action of nitrogen-containing bisphosphonates (N-BPs). ZOL, however, has also been reported to inhibit the proliferation of regulatory T cells in vitro and to reduce the expression of Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), a negative regulator of T cell activation that is increased in patients with autoimmune diseases. There are, however, no data on the relationship between ZOL treatment and soluble(s)CTLA-4 either in vivo in relevant patient populations or in vitro with the use of assays relevant to the mechanism of action of N-BPs. The objectives of the present study were firstly, to characterize the ZOL-induced APR in patients with inflammatory rheumatic diseases (IRDs) and its relationship with changes in circulating sCTLA-4 and secondly, to investigate the effects of ZOL on CTLA-4 production and expression by peripheral blood mononuclear cells (PBMCs). We studied 10 postmenopausal women with IRDs treated with intravenous ZOL 5 mg. Five women experienced APR (APR + ) associated with significant decreases in blood lymphocytes and increases in granulocytes and serum CRP. Serum sCTLA-4 values were increased in all patients before ZOL administration and decreased significantly 72 h after the ZOL infusion (from 30.0 +/- 2.9 to 6.3 +/- 1.8 ng/ml; p < 0.001) with no differences between APR + and APR- patients. Consistent with the results of the in vivo study, ZOL (1 mu M) decreased the production of sCTLA-4 by 87% and 57% after 3 and 5 days in cultures of peripheral blood mononuclear cells (PBMCs) in vitro, respectively, and inhibited the expression of both cytoplasmic and membrane-bound CTLA-4. Our results reveal a novel immunoregulatory action of ZOL that is not related to its action on bone resorption but might be associated with reported clinically significant extraskeletal outcomes of ZOL treatment. Show less
Pamidronate [3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APD)] was the first nitrogen-containing bisphosphonate (N-BP) investigated in clinical studies. In contrast to other clinically used... Show morePamidronate [3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APD)] was the first nitrogen-containing bisphosphonate (N-BP) investigated in clinical studies. In contrast to other clinically used bisphosphonates, pamidronate was discovered and its properties were initially studied in an Academic Institution. On the occasion of the 50th Anniversary of the first publications on the biological effects of bisphosphonates, I review in this article the contribution of Leiden investigators to the development of pamidronate that led to the recognition of the significance of the Nitrogen atom in the side chain of bisphosphonates for their action on bone resorption and to the formulation of principles for the use of N-BPs in the management of patients with different skeletal disorders. Show less
Effects on bone material properties of two-year antiosteoporotic treatment were assessed using in vivo impact microindentation (IMI) in patients with low bone mineral density (BMD) values.... Show moreEffects on bone material properties of two-year antiosteoporotic treatment were assessed using in vivo impact microindentation (IMI) in patients with low bone mineral density (BMD) values. Antiresorptive treatment, in contrast to vitamin D +/- calcium treatment alone, induced BMD-independent increases in bone material strength index, measured by IMI, the magnitude of which depended on pretreatment values.Introduction Bone material strength index (BMSi), measured by IMI in vivo, is reduced in patients with fragility fractures, but there is no information about changes in values during long-term therapy. In the present study, we assessed changes in BMSi in patients receiving antiosteoporotic treatments for periods longer than 12 months.Methods We included treatment-naive patients with low bone mass who had a BMSi measurement with OsteoProbe (R) at presentation and consented to a repeat measurement after treatment. Results We studied 54 patients (34 women), median age 58 years, of whom 30 were treated with bisphosphonates or denosumab (treatment group) and 24 with vitamin D +/- calcium alone (control group). There were no differences in clinical characteristics between the two groups with the exception of a higher number of previous fragility fractures in the treatment group. Baseline hip BMD and BMSi values were lower in the treatment group. After 23.1 +/- 6.6 months, BMSi increased significantly in the treatment group (82.4 +/- 4.3 vs 79.3 +/- 4.1;p < 0.001), but did not change in the control group (81.5 +/- 5.2 vs 82.2 +/- 4.1;p = 0.35). Changes in BMSi with antiresorptives were inversely related with baseline values (r = - 0.43;p = 0.02) but not with changes in BMD. Two patients in the control group with large decreases in BMSi values sustained incident fractures.Conclusion In patients at increased fracture risk, antiresorptive treatments induced BMD-independent increases in BMSi values, the magnitude of which depended on pretreatment values. Show less
Background Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal... Show moreBackground Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis.Methods The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between -2.5 and -4.0 if no previous radiographic vertebral fracture, or between -1.5 and -4.0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than -4.0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66).Findings Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36.5 months (IQR 34.43-40.15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47.6 months, IQR 35.45-60.06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3.7% (251/6770) versus 7.8% (542/6910), hazard ratio (HR) 0.46, 95% CI 0.40-0.53; hip fractures 0.8% (65/8043) versus 1.6% (125/8028), 0.53, 0.39-0.71; non-vertebral fractures 5.1% (412/8043) versus 6.7% (541/8028), 0.77, 0.68-0.87; all p<0.0001. Combined results from LOFT plus LOFT Extension for cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 4.9% (341/6909) versus 9.6% (675/7011), HR 0.48, 95% CI 0.42-0.55; hip fractures 1.1% (86/8043) versus 2.0% (162/8028), 0.52, 0.40-0.67; non-vertebral fractures 6.4% (512/8043) versus 8.4% (675/8028), 0.74, 0.66-0.83; all p<0.0001. In LOFT, the composite cardiovascular endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 273 (3.4%) of 8043 patients in the odanacatib group versus 245 (3.1%) of 8028 in the placebo group (HR 1.12, 95% CI 0.95-1.34; p=0.18). New-onset atrial fibrillation or flutter occurred in 112 (1.4%) of 8043 patients in the odanacatib group versus 96 (1.2%) of 8028 in the placebo group (HR 1.18, 0.90-1.55; p=0.24). Odanacatib was associated with an increased risk of stroke (1.7% [136/8043] vs 1.3% [104/8028], HR 1.32, 1.02-1.70; p=0.034), but not myocardial infarction (0.7% [60/8043] vs 0.9% [74/8028], HR 0.82, 0.58-1.15; p=0.26). The HR for all-cause mortality was 1.13 (5.0% [401/8043] vs 4.4% [356/8028], 0.98-1.30; p=0.10). When data from LOFT Extension were included, the composite of cardiovascular death, myocardial infarction, or stroke occurred in significantly more patients in the odanacatib group than in the placebo group (401 [5.0%] of 8043 vs 343 [4.3%] of 8028, HR 1.17, 1.02-1.36; p=0.029, as did stroke (2.3% [187/8043] vs 1.7% [137/8028], HR 1.37, 1.10-1.71; p=0.0051).Interpretation Odanacatib reduced the risk of fracture, but was associated with an increased risk of cardiovascular events, specifically stroke, in postmenopausal women with osteoporosis. Based on the overall balance between benefit and risk, the study's sponsor decided that they would no longer pursue development of odanacatib for treatment of osteoporosis. Copyright (C) 2019 Elsevier Ltd. All rights reserved. Show less
Context: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone disorder commonly treated with bisphosphonates, but clinical and biochemical responses may be incomplete.Objective: To... Show moreContext: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone disorder commonly treated with bisphosphonates, but clinical and biochemical responses may be incomplete.Objective: To evaluate the efficacy and tolerability of the receptor activator of nuclear factor-kappa B ligand inhibitor denosumab in the treatment of patients with FD/MAS refractory to bisphosphonate therapy.Design: Case series.Setting: Academic center of expertise for rare bone diseases.Patients: Data were collected from 12 consecutive patients with FD/MAS with persistent pain and increased biochemical markers of bone turnover (BTMs) after long-term treatment with bisphosphonates (median, 8.8 years) and were treated with subcutaneous denosumab 60 mg at 3- or 6-month intervals with a follow-up for at least 12 months.Main outcome(s): Sustained reduction of BTMs and bone pain.Results: A 60 mg dose of denosumab once every 3 months, but not once every 6 months, induced a sustained reduction of BTMs. After a median treatment period of 15.5 months (range, 12 to 19) serum alkaline phosphatase activity and propeptide of type 1 procollagen levels were respectively reduced from 212 +/- 39.4 IU/L to 79 +/- 6.0 IU/L (P = 0.004) and from 346.2 +/- 111.1 ng/mL to 55.7 +/- 16.6 ng/mL (P = 0.023) and normalized in 70% and 75% of patients, respectively. Although not quantitavely measured, 10 patients reported a reduction in bone pain of whom 6 reported complete elimination of pain. Treatment with denosumab was well tolerated.Conclusion: Our results indicate that 60 mg of denosumab every 3 months is a promising, welltolerated treatment of most patients with FD/MAS refractory to bisphosphonate therapy. These results together with those of previously published case reports provide the necessary background for the design of a larger, controlled study. Show less
Objective: Familial Paget's disease of bone is inherited as an autosomal-dominant trait and mutations in the sequestosome 1 (SQSTM1) gene have been reported with variable frequency in patients with... Show moreObjective: Familial Paget's disease of bone is inherited as an autosomal-dominant trait and mutations in the sequestosome 1 (SQSTM1) gene have been reported with variable frequency in patients with familial disease. The natural history, however, of the disease in family members with or without SQSTM1 mutations is unknown.Methods: To address this question, we investigated members of families with Paget's disease identified and genotyped in 2000 in The Netherlands without clinical, biochemical or radiological signs of Paget's disease. Seventy-five subjects, median age 56 years (range 44-93), with or without SQSTM1 mutations participated in the present study. Medical history was obtained and clinical examination and laboratory investigations were performed in all. When serum biochemical markers of bone turnover were increased, skeletal scintigraphy with SPECT-CT was performed.Results: After a mean period of 15.9 +/- 0.32 (SD) years no subject without SQSTM1 mutations (either from positive or negative families) developed Paget's disease. Of 14 carriers of SQSTM1 mutations, Paget's disease of the pelvis was diagnosed in a 74-year old asymptomatic woman.Conclusion: The incidence of new Paget's disease in SQSTM1 positive subjects was 7.1% and no mutation-negative subject developed the disease within 16 years of follow-up. Subjects without SQSTM1 mutations can be reassured whereas mutation carriers should consider screening. Our findings should be confirmed in other populations as currently unknown environmental factors that might be involved in the development of the disease may differ. Show less
Cessation of denosumab treatment is associated with increases in bone turnover above baseline values and rapid bone loss. We investigated the efficacy of zoledronate to prevent this bone loss in... Show moreCessation of denosumab treatment is associated with increases in bone turnover above baseline values and rapid bone loss. We investigated the efficacy of zoledronate to prevent this bone loss in women with postmenopausal osteoporosis who were treated with denosumab (mean duration 2.2 years) and discontinued treatment after achieving osteopenia. Women were randomized to receive a single 5-mg infusion of zoledronate (ZOL) (n = 27) or two additional 60-mg injections of denosumab (Dmab) (n = 30). Both groups were followed for a total period of 24 months. At 24 months lumbar spine-bone mineral density (LS-BMD) was not different from baseline in the ZOL group, but decreased in the Dmab group by (mean +/- SD) 4.82% +/- 0.7% (p < 0.001) from the 12-month value; the difference in BMD changes between the two groups, the primary endpoint of the study, was statistically significant (p = 0.025). Results of femoral neck (FN)-BMD changes were similar. ZOL infusion was followed by small but significant increases in serum procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) during the first year and stabilization thereafter. In the Dmab group, bone turnover marker values did not change during the first 12 months but increased significantly at 15 months and in the majority of women these remained elevated at 24 months. Neither baseline nor 12-month bone turnover marker values were associated with BMD changes in either group of women. In the Dmab group, three patients sustained vertebral fractures (two patients multiple clinical, one patient morphometric) whereas one patient in the ZOL group sustained clinical vertebral fractures 12 months after the infusion. In conclusion, a single intravenous infusion of ZOL given 6 months after the last Dmab injection prevents bone loss for at least 2 years independently of the rate of bone turnover. Follow-up is recommended, because in a few patients ZOL treatment might not have the expected effect at 2 years. (c) 2019 American Society for Bone and Mineral Research. Show less
Objective: To evaluate, post hoc, the efficacy and safety of abaloparatide by degree of renal impairment. Methods: ACTIVE was a phase 3, 18-month, randomized, double-blind, active-comparator,... Show moreObjective: To evaluate, post hoc, the efficacy and safety of abaloparatide by degree of renal impairment. Methods: ACTIVE was a phase 3, 18-month, randomized, double-blind, active-comparator, placebo-controlled study of postmenopausal women with osteoporosis who received subcutaneous abaloparatide 80 mu g, placebo, or open-label teriparatide 20 mu g daily. Patients with serum creatinine >2.0 mg/dL or 1.5-2.0 mg/dL with an estimated glomerular filtration rate (eGFR) <37 mL/min, calculated by Cockcroft-Gault formula, were excluded. Results: At baseline, 660 patients had eGFR >= 90 mL/min, 1276 had 60 to <90 mL/min, and 527 had <60 mL/min. Older age and lower T-scores were associated with greater renal impairment. Among renal-function subgroups, there were no meaningful changes in bone mineral density, fracture risk reduction, or overall incidence of treatment-emergent adverse events in the active-treatment arms. Anemia, nausea, hypercalcemia, and upper-respiratory-tract infection tended to be more frequent with increasing renal impairment. Hypercalcemia measured by albumin-adjusted serum calcium occurred significantly less frequently with abaloparatide than teriparatide in patients with eGFR <60 mL/min (3.6% versus 10.9%; p = .008) and in the overall ACTIVE safety population (3.4% versus 6.4%; p = .006). Computed tomography scans in 376 patients revealed no evidence of increased renal calcification. Conclusion: Increased exposure to abaloparatide and teriparatide in patients with renal impairment led to no meaningful differences in efficacy or safety. These results support the use of abaloparatide without dosage adjustment in patients with renal impairment, provided those with severe renal impairments are monitored for adverse events. Show less
