Treatment patterns in women with postmenopausal osteoporosis using abaloparatide: a real-world observational study.

Review of medical records from 173 women with osteoporosis who received abaloparatide treatment revealed that 96.0% had at least one visit for osteoporosis management and 55.5% had medication support group access. The most common reasons for discontinuing treatment were financial (31.2%) and tolerability (22.8%). Most patients (64.8%) completed treatment as prescribed. PURPOSE: Abaloparatide is approved for the treatment of women with postmenopausal osteoporosis at high risk for fracture. This study evaluated real-world treatment patterns for patients new to abaloparatide, regardless of osteoporosis treatment history. METHODS: Data for patients with ≥ 1 prescription for abaloparatide were collected retrospectively from six academic and clinical practice settings across the US. RESULTS: A total of 173 patients were enrolled (mean [SD] age, 69.8 [7.4] years). At the time of abaloparatide treatment initiation, 78.6% had received other osteoporosis medications. Mean (SD) time from discontinuation of osteoporosis medications prior to initiation of abaloparatide was 1.7 (3.2) years. Twenty-four months of follow-up data from the initiation date of abaloparatide was collected from 94.0% of patients and 6.0% of patients had 12-24 months of follow-up. During the follow-up period, 96.0% of patients had at least one visit for osteoporosis management and 55.5% had access to a medication support program. The median duration of therapy was 18.6 months and 105/162 (64.8%) completed abaloparatide treatment as prescribed. The most common reasons for treatment discontinuation were financial (31.2%) and tolerability (22.8%). Following completion of a course of treatment with abaloparatide, 82/162 (50.6%) patients transitioned to another osteoporosis medication. The median time between abaloparatide treatment course completion and the initiation of follow-on medication was 21 days. CONCLUSION: Most patients completed treatment with abaloparatide as prescribed, and over half continued with an antiresorptive agent. This favorable conduct may be the result of regular follow-up visits and accessibility to both medication and patient support services.

Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the HPP International Working Group.

Hypophosphatasia (HPP) is a rare inborn error of metabolism that presents variably in both age of onset and severity. HPP is caused by pathogenic variants in the ALPL gene, resulting in low activity of tissue nonspecific alkaline phosphatase (TNSALP). Patients with HPP tend have a similar pattern of elevation of natural substrates that can be used to aid in diagnosis. No formal diagnostic guidelines currently exist for the diagnosis of this condition in children, adolescents, or adults. The International HPP Working Group is a comprised of a multidisciplinary team of experts from Europe and North America who have expertise in the diagnosis and management of patients with HPP. This group reviewed 93 papers through a Medline, Medline In-Process, and Embase search for the terms "HPP" and "hypophosphatasia" between 2005 and 2020 and that explicitly address either the diagnosis of HPP in children, clinical manifestations of HPP in children, or both. Two reviewers independently evaluated each full-text publication for eligibility and studies were included if they were narrative reviews or case series/reports that concerned diagnosis of pediatric HPP or included clinical aspects of patients diagnosed with HPP. This review focused on 15 initial clinical manifestations that were selected by a group of clinical experts.The highest agreement in included literature was for pathogenic or likely pathogenic ALPL variant, elevation of natural substrates, and early loss of primary teeth. The highest prevalence was similar, including these same three parameters and including decreased bone mineral density. Additional parameters had less agreement and were less prevalent. These were organized into three major and six minor criteria, with diagnosis of HPP being made when two major or one major and two minor criteria are present.

Impact of an Electronic Decision Support Tool to Improve Ophthalmic Safety in Hydroxychloroquine Prescribing Practices.

BACKGROUND AND OBJECTIVE: The purpose of this study was to implement a clinical decision support tool (CDS) and assess its impact on adherence to 2016 American Academy of Ophthalmology (AAO) hydroxychloroquine dosing recommendations. PATIENTS AND METHODS: This retrospective, interventional study implemented an automated alert to calculate maximum daily hydroxychloroquine dose based on 2016 AAO recommendations and flag noncompliant orders. Prevalence of excessive dosing after CDS implementation was assessed. RESULTS: A total of 7,417 patients met inclusion criteria. After intervention, prevalence of excessive dosing decreased from 27.4% to 21.1% (P < .001) among all prescriptions and from 26.8% to 16.2% (P < .001) among new prescriptions. Daily doses exceeding 400 mg decreased from 0.8% to 0.02% (P < .001). Risk factors for excessive dosing included low weight (odds ratio, 75.6 [95% CI, 54.0 to 105.8]) and nonrheumatologist prescriber (odds ratio, 1.60 to 3.63; all P < .005). CONCLUSIONS: This study highlights the efficacy of a CDS in reducing excessive hydroxychloroquine dosing and improving adherence to AAO ophthalmic safety guidelines. [Ophthalmic Surg Lasers Imaging 2022;53:310-316.].

Abaloparatide followed by alendronate in women ≥80 years with osteoporosis: post hoc analysis of ACTIVExtend.

OBJECTIVE: Fracture risk increases with age, but few studies focus on persons ≥80 years. In the ACTIVE trial, treatment with abaloparatide for 18 months reduced osteoporotic fracture risk and increased bone mineral density. These effects were maintained with 24 months alendronate treatment in ACTIVExtend. We postulated that similar improvements in bone mineral density and safety would be demonstrated in women ≥80 years. METHODS: Post hoc analyses of bone mineral density and fracture incidence in women with osteoporosis at high risk of fracture ≥80 years from ACTIVExtend. RESULTS: In total, 56 women aged ≥80 years at ACTIVE baseline entered the ACTIVExtend study; 46 of these completed the study. Mean age was 83.3 years; other baseline characteristics were similar. At the end of ACTIVE, bone mineral density increased at all sites for abaloparatide versus placebo. Bone mineral density increased in parallel in both groups during alendronate therapy (19 to 43 months) in ACTIVExtend. At month 43, mean percent change in bone mineral density from baseline was 17.2% abaloparatide/alendronate versus 8.6% placebo/alendronate (P < 0.0001) at the lumbar spine, 5.3% abaloparatide/alendronate versus 3.0% placebo/alendronate (P = 0.024) at the total hip, and 4.6% abaloparatide/alendronate versus 3.1% placebo/alendronate (P = 0.044) at the femoral neck. Fracture incidence was low and did not differ significantly between groups. Sequential treatment with abaloparatide followed by alendronate was well tolerated; the proportion of participants reporting adverse events was similar between groups. CONCLUSIONS: Sequential treatment with abaloparatide followed by alendronate (43 months follow-up) in this small subgroup of ACTIVExtend participants suggests abaloparatide is well tolerated and effective in women aged ≥80 years. : Video Summary:http://links.lww.com/MENO/A618.

Video Summary:http://links.lww.com/MENO/A618.

Special Article: 2018 American College of Rheumatology/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis.

OBJECTIVE: To develop an evidence-based guideline for the pharmacologic and nonpharmacologic treatment of psoriatic arthritis (PsA), as a collaboration between the American College of Rheumatology (ACR) and the National Psoriasis Foundation (NPF). METHODS: We identified critical outcomes in PsA and clinically relevant PICO (population/intervention/comparator/outcomes) questions. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available pharmacologic and nonpharmacologic therapies for PsA. GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to rate the quality of the evidence. A voting panel, including rheumatologists, dermatologists, other health professionals, and patients, achieved consensus on the direction and the strength of the recommendations. RESULTS: The guideline covers the management of active PsA in patients who are treatment-naive and those who continue to have active PsA despite treatment, and addresses the use of oral small molecules, tumor necrosis factor inhibitors, interleukin-12/23 inhibitors (IL-12/23i), IL-17 inhibitors, CTLA4-Ig (abatacept), and a JAK inhibitor (tofacitinib). We also developed recommendations for psoriatic spondylitis, predominant enthesitis, and treatment in the presence of concomitant inflammatory bowel disease, diabetes, or serious infections. We formulated recommendations for a treat-to-target strategy, vaccinations, and nonpharmacologic therapies. Six percent of the recommendations were strong and 94% conditional, indicating the importance of active discussion between the health care provider and the patient to choose the optimal treatment. CONCLUSION: The 2018 ACR/NPF PsA guideline serves as a tool for health care providers and patients in the selection of appropriate therapy in common clinical scenarios. Best treatment decisions consider each individual patient situation. The guideline is not meant to be proscriptive and should not be used to limit treatment options for patients with PsA.

Special Article: 2018 American College of Rheumatology/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis.

OBJECTIVE: To develop an evidence-based guideline for the pharmacologic and nonpharmacologic treatment of psoriatic arthritis (PsA), as a collaboration between the American College of Rheumatology (ACR) and the National Psoriasis Foundation (NPF). METHODS: We identified critical outcomes in PsA and clinically relevant PICO (population/intervention/comparator/outcomes) questions. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available pharmacologic and nonpharmacologic therapies for PsA. GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to rate the quality of the evidence. A voting panel, including rheumatologists, dermatologists, other health professionals, and patients, achieved consensus on the direction and the strength of the recommendations. RESULTS: The guideline covers the management of active PsA in patients who are treatment-naive and those who continue to have active PsA despite treatment, and addresses the use of oral small molecules, tumor necrosis factor inhibitors, interleukin-12/23 inhibitors (IL-12/23i), IL-17 inhibitors, CTLA4-Ig (abatacept), and a JAK inhibitor (tofacitinib). We also developed recommendations for psoriatic spondylitis, predominant enthesitis, and treatment in the presence of concomitant inflammatory bowel disease, diabetes, or serious infections. We formulated recommendations for a treat-to-target strategy, vaccinations, and nonpharmacologic therapies. Six percent of the recommendations were strong and 94% conditional, indicating the importance of active discussion between the health care provider and the patient to choose the optimal treatment. CONCLUSION: The 2018 ACR/NPF PsA guideline serves as a tool for health care providers and patients in the selection of appropriate therapy in common clinical scenarios. Best treatment decisions consider each individual patient situation. The guideline is not meant to be proscriptive and should not be used to limit treatment options for patients with PsA.

Indications of DXA in women younger than 65 yr and men younger than 70 yr: the 2013 Official Positions.

Dual-energy X-ray absorptiometry (DXA) is the method of choice to assess fracture risk for women 65 yr and older and men 70 yr and older. The 2007 International Society for Clinical Densitometry Official Positions had developed guidelines for assessing bone density in younger women during and after the menopausal transition and in men 50-69 yr and the 2008 National Osteoporosis Foundation (NOF) guidelines recommended testing in postmenopausal women younger than 65 yr and men 50-69 yr only in the presence of clinical risk factors. The purpose of the 2013 DXA Task Force was to reassess the NOF guidelines for ordering DXA in postmenopausal women younger than 65 yr and men 50-69 yr. The Task Force reviewed the literature published since the 2007 Position Development Conference and 2008 NOF, reviewing clinical decision rules such as the Osteoporosis Screening Tool and FRAX and sought to keep recommendations simple to remember and implement. Based on this assessment, the NOF guidelines were endorsed; DXA was recommended in those postmenopausal women younger than 65 yr and men 50-69 yr only in the presence of clinical risk factors for low bone mass, such as low body weight, prior fracture, high-risk medication use, or a disease or condition associated with bone loss.

Future therapeutic targets in osteoporosis.

PURPOSE OF REVIEW: To describe new agents for the treatment of osteoporosis, discuss a conceptual framework of agents that are antiresorptive or anabolic, and review pathways that affect bone turnover and steps in those pathways that are targets for new therapeutic agents. RECENT FINDINGS: Novel antiresorptive agents are being developed. Denosumab, a fully human mononoclonal antibody to receptor activator of nuclear factor kappa B ligand, has completed its major fracture trial. Assessment of odanacatib, an inhibitor of cathepsin K, an osteoclast enzyme required for resorption of bone matrix, is underway. Glucagon-like peptide 2 is an intestinal peptide that prevents the nocturnal rise in bone resorption. Anabolic agents act by stimulating new bone formation. Novel anabolic agents in development include antibodies that target molecules (sclerostin and Dkk1) involved in Wnt signaling, a pathway that regulates gene transcription of proteins that are important for osteoblast function. An antagonist to the calcium-sensing receptor and an activin receptor fusion protein, which functions as an activin antagonist, have shown promise as anabolic agents in early human trials. SUMMARY: This review discusses potential future advances in drug therapy for osteoporosis including novel antiresorptive and anabolic agents that may become available in the coming years.

Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial.

Denosumab is a fully human monoclonal antibody that inhibits bone resorption by neutralizing RANKL, a key mediator of osteoclast formation, function, and survival. This phase 3, multicenter, doubleblind study compared the efficacy and safety of denosumab with alendronate in postmenopausal women with low bone mass. One thousand one hundred eighty-nine postmenopausal women with a T-score

Potential new drug targets for osteoporosis.

Osteoporosis is a worldwide health problem with a high prevalence. Agents for the treatment of osteoporosis are classified as either antiresorptive or anabolic. Antiresorptive agents work by inhibiting the activity of osteoclasts and, therefore, reducing bone resorption. Currently available antiresorptive agents include bisphosphonates, selective estrogen-receptor modulators, calcitonin and estrogen. Various novel antiresorptive agents are in development. Receptor activator of nuclear factor kappa B ligand is an important cytokine involved in osteoclast activation; denosumab, a fully human monoclonal antibody to this molecule, has finished a major fracture trial. Assessment is underway of odanacatib--an inhibitor of cathepsin K, which is an osteoclast enzyme required for resorption of bone matrix. Glucagon-like peptide 2 is being evaluated for the prevention of the nocturnal rise in bone resorption without affecting bone formation. Anabolic agents act by stimulating formation of new bone. The only anabolic agent currently available in the US is teriparatide--recombinant human parathyroid hormone (PTH)(1-34)--and recombinant human PTH(1-84) is available in Europe. PTH stimulates osteoblast function and bone formation. Novel anabolic agents in development include: antibodies such as sclerostin and dickkopf-1 that target molecules involved in Wnt signaling, a pathway that regulates gene transcription of proteins that are important for osteoblast function; an antagonist to the calcium-sensing receptor; and an activin receptor fusion protein, which functions as an activin antagonist and has shown promise as an anabolic agent in early human trials.

Adult hypophosphatasia treated with teriparatide.

INTRODUCTION: Hypophosphatasia (HPP) features low serum alkaline phosphatase (ALP) activity (hypophosphatasemia) due to loss-of-function mutation within TNSALP, the gene that encodes "tissue-nonspecific" ALP (TNSALP). Consequently, inorganic pyrophosphate accumulates extracellularly and impairs skeletal mineralization. Affected adults manifest osteomalacia, often with slowly healing metatarsal stress fractures (MTSFs) and proximal femur pseudofractures. Pharmacotherapy remains elusive. PATIENT AND METHODS: A middle-aged woman sustained a slowly healing MTSF and then two enlarging MTSFs and a spontaneous proximal femur fracture. Pain persisted at all fracture sites. HPP was diagnosed as a result of low ALP activity (10-24 IU/liter; normal, 40-150 IU/liter) and elevated inorganic phosphate and pyridoxal 5'-phosphate concentrations in serum. Teriparatide (TPTD) (recombinant human PTH 1-34), 20 microg, was injected sc daily in an attempt to enhance osteoblast synthesis of TNSALP. RESULTS: Six weeks later, all fracture pain improved, and it resolved after 4 months. Radiographs of the enlarging MTSFs showed repair after 2-4 months. The femur fracture partially mended after 2 months and then healed. Additionally, hypophosphatasemia and hyperphosphatemia corrected, and biochemical markers of bone remodeling increased as long as TPTD (given for 18 months) was continued. The patient carried a heterozygous TNSALP missense mutation, p.D378V, which is common in the United States. CONCLUSION: This first HPP patient given TPTD demonstrated fracture repair accompanying correction of hypophosphatasemia and hyperphosphatemia and bone marker responses indicating enhanced skeletal remodeling. Increased TNSALP synthesis in bone together with lowered extracellular concentrations of inorganic phosphate (a competitive inhibitor of ALPs) seemed to improve her skeletal mineralization. Further evaluation of TPTD for HPP is warranted.

Raloxifene: a selective estrogen-receptor modulator for postmenopausal osteoporosis - a clinical update on efficacy and safety.

Selective estrogen-receptor modulators are molecules with specific estrogen-receptor binding affinity. Each selective estrogen-receptor modulator induces a unique conformation in the ligand-receptor complex, which leads to transcriptional activation and/or inhibition. Raloxifene 60 mg/day, a benzothiophene selective estrogen-receptor modulator, is approved for the prevention and treatment of postmenopausal osteoporosis. This article provides an update on new studies and further analyses of clinical trial data for raloxifene. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial of women with osteoporosis has described the efficacy of raloxifene in decreasing vertebral fracture risk over 4 years. The Continuing Outcomes Relevant to Evista((R)) (CORE) trial, designed to assess the effects of raloxifene on breast cancer prevention, is a 4-year continuation of MORE. The skeletal and cardiovascular effects of raloxifene in the CORE study were similar to those observed in MORE. The relative risk of developing breast cancer was significantly decreased in women treated with raloxifene, compared with placebo, after 4 years in MORE and 8 years in the CORE trial. The incidence of uterine bleeding, endometrial hyperplasia and endometrial cancer was similar between raloxifene and placebo after 8 years of treatment. Raloxifene use is associated with a higher incidence of hot flashes and leg cramps, and an increased risk of venous thromboembolic events.

Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: results from a 6-month double-blind placebo-controlled trial.

UNLABELLED: We compared combination treatment with teriparatide plus raloxifene with teriparatide alone in women with postmenopausal osteoporosis in a 6-month double-blind, placebo-controlled trial that measured biochemical markers of bone turnover and BMD. Markers of bone formation and spine BMD increased similarly with teriparatide alone and combination therapy. However, combination therapy induced a significantly smaller increase in bone resorption versus teriparatide alone and significantly increased total hip BMD versus baseline. INTRODUCTION: The effects of combining two approved treatments for osteoporosis with different modes of action were examined by comparing teriparatide [rhPTH(1-34)] monotherapy with combination teriparatide and raloxifene therapy. MATERIALS AND METHODS: A 6-month randomized, double-blind trial comparing teriparatide plus raloxifene (n = 69) versus teriparatide plus placebo (n = 68) was conducted in postmenopausal women with osteoporosis. RESULTS: Bone formation (N-terminal propeptide of type 1 collagen [PINP]) increased similarly in both treatment groups. However, the increase in bone resorption (serum C-terminal telopeptide of type I collagen [CTx]) in the combination group was significantly smaller than in the teriparatide-alone group (p = 0.015). Lumbar spine BMD significantly increased 5.19 +/- 0.67% from baseline in the teriparatide-alone group. In the combination group, lumbar spine (6.19 +/- 0.65%), femoral neck (2.23 +/- 0.64%), and total hip (2.31 +/- 0.56%) BMD significantly increased from baseline to study endpoint, and the increase in total hip BMD was significantly greater than in the teriparatide-alone group (p = 0.04). In the teriparatide-alone group, mean serum calcium levels increased from baseline to endpoint (0.30 +/- 0.06 mg/dl, p < 0.001), whereas mean serum phosphate remained unchanged. In the combination group, mean serum calcium was unchanged, and mean serum phosphate decreased (-0.20 +/- 0.06 mg/dl, p < 0.001) from baseline to endpoint. Changes in serum calcium (p < 0.001) and phosphate (p < 0.004) were significantly different between treatment groups. The safety profile of combination therapy was similar to teriparatide alone. CONCLUSIONS: Combination therapy increased bone formation to a similar degree as teriparatide alone. However, the increase in bone resorption was significantly less and total hip BMD significantly increased for combination therapy compared with teriparatide alone. Combination treatment with raloxifene may thus enhance the bone forming effects of teriparatide. Further studies over longer treatment duration that include fracture endpoints are necessary to fully ascertain the clinical significance of combination raloxifene plus teriparatide therapy in postmenopausal osteoporosis.

The use of intermittent human parathyroid hormone as a treatment for osteoporosis.

Parathyroid hormone (PTH), given intermittently, is an anabolic agent. PTH has been demonstrated to increase bone mass and reduce vertebral and nonvertebral fractures, and has been approved for use in the US and Europe. PTH is a genetically engineered 34 amino acid protein with the designation teriparatide (recombinant DNA origin) or recombinant human PTH 1-34. A recombinant DNA preparation with all 84 amino acids of the native PTH molecule is in clinical trials. These PTH preparations are self-administered daily injections, and it is approved for women and men at high risk for fractures, including patients with prevalent fractures, low bone mass, and multiple risk factors. PTH is likely to be used most frequently in patients who fracture on therapy, but can be used in high-risk treatment-naïve patients. Previous treatment with alendronate appears to impair the anabolic response of PTH preparations. Patients who have Paget's disease, prior radiation therapy to the skeleton, as well as children and young adults with open epiphyses, are at higher risk for osteosarcoma and should not be given PTH. Patients with hypercalcemia and hyperparathyroidism also should not receive the drug.