Can we identify patients with high risk of osteoarthritis progression who will respond to treatment? A focus on epidemiology and phenotype of osteoarthritis

Osteoarthritis is a syndrome affecting a variety of patient profiles. A European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis and the European Union Geriatric Medicine Society working meeting explored the possibility of identifying different patient profiles in osteoarthritis. The risk factors for the development of osteoarthritis include systemic factors (e.g., age, sex, obesity, genetics, race, and bone density) and local biomechanical factors (e.g., obesity, sport, joint injury, and muscle weakness); most also predict disease progression, particularly joint injury, malalignment, and synovitis/effusion. The characterization of patient profiles should help to better orientate research, facilitate trial design, and define which patients are the most likely to benefit from treatment. There are a number of profile candidates. Generalized, polyarticular osteoarthritis and local, monoarticular osteoarthritis appear to be two different profiles; the former is a feature of osteoarthritis co-morbid with inflammation or the metabolic syndrome, while the latter is more typical of post-trauma osteoarthritis, especially in cases with severe malalignment. Other biomechanical factors may also define profiles, such as joint malalignment, loss of meniscal function, and ligament injury. Early- and late-stage osteoarthritis appear as separate profiles, notably in terms of treatment response. Finally, there is evidence that there are two separate profiles related to lesions in the subchondral bone, which may determine benefit from bone-active treatments. Decisions on appropriate therapy should be made considering clinical presentation, underlying pathophysiology, and stage of disease. Identification of patient profiles may lead to more personalized healthcare, with more targeted treatment for osteoarthritis

Zoledronate in the prevention of Paget's (ZiPP) : protocol for a randomised trial of genetic testing and targeted zoledronic acid therapy to prevent SQSTM1-mediated Paget's disease of bone.

Introduction Paget’s disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget’s disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carry SQSTM1 mutations. Methods and analysis People with a family history of PDB aged >30 years who test positive for SQSTM1 mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be measured and questionnaires completed to assess pain, health-related quality of life (HRQoL), anxiety and depression. Participants will be randomised to receive a single intravenous infusion of 5 mg ZA or placebo and followed up annually for between 4 and 8 years at which point baseline assessments will be repeated. The primary endpoint will be new bone lesions assessed by radionuclide bone scan. Secondary endpoints will include changes in biochemical markers of bone turnover, pain, HRQoL, anxiety, depression and PDB-related skeletal events

Risedronate increases bone density and reduces vertebral fracture risk within one year in men on corticosteroid therapy.

Limited information is available on the effect of bisphosphonates in men receiving corticosteroid therapy. We studied 184 men among the patients enrolled in two, double-blind, placebo-controlled, 1-year studies with similar protocols. The studies evaluated the effects of risedronate in patients beginning corticosteroid treatment at a dose of at least 7.5 mg per day of prednisone or equivalent (prevention study) or continuing long-term treatment of corticosteroid at that dose (treatment study). The men received either placebo or risedronate (2.5 mg or 5 mg) daily, along with calcium supplementation (500-1000 mg). Endpoints included differences in bone mineral density (BMD) at the lumbar spine, femoral neck, and femoral trochanter, assessment of vertebral fractures, changes in biochemical markers of bone turnover, and overall safety. In the treatment study, risedronate 5 mg significantly (P < 0.01) increased lumbar spine BMD by 4.8% at the lumbar spine, 2.1% at the femoral neck, and 2.6% at the femoral trochanter compared with baseline values. In the prevention study, bone loss was prevented with risedronate 5 mg; in the placebo group, BMD decreased significantly (P < 0.01) by 3.4%, 3.3%, and 3.4% in the lumbar spine, femoral neck, and trochanter, respectively, at 1 year. The differences between risedronate 5 mg and placebo groups were significant at all skeletal sites in the prevention study (P < 0.01) and at the lumbar spine in the treatment study (P < 0.001). The 2.5 mg dose also had a positive effect on BMD, although of a lesser magnitude than the 5 mg dose. When the data from the two studies were combined, the incidence of vertebral fractures decreased 82.4% (95% confidence interval, 36.6%-95.1%) in the pooled risedronate groups compared with placebo (P = 0.008). Risedronate was well tolerated in men, with a similar incidence of upper gastrointestinal adverse events in the placebo and treatment groups. Daily treatment with risedronate increases bone density and decreases vertebral fracture risk within 1 year in men receiving corticosteroid therapy

Zoledronic acid once-yearly: What role in the prevention of non-vertebral osteoporotic fractures?

Osteoporosis is the most common bone disease. Low levels of oestrogens or testosterone are risk factors for primary osteoporosis. The most common cause of secondary osteoporosis is glucocorticoid treatment, but there are many other secondary causes of osteoporosis. Osteoporosis can be secondary to anti-oestrogen treatment for hormone-sensitive breast cancer and to androgen-deprivation therapy for prostate cancer. Zoledronic is the most potent bisphosphonate at inhibiting bone resorption. In osteoporosis, zoledronic acid increases bone mineral density for at least a year after a single intravenous administration. The efficacy and safety of extended release (once-yearly) zoledronic acid in the treatment of osteoporosis is reviewed

Renal expression of parvalbumin is critical for NaCl handling and response to diuretics.

Contains fulltext : 51558.pdf (publisher's version ) (Closed access)The distal convoluted tubule (DCT) plays an essential role in the reabsorption of NaCl by the kidney, a process that can be inhibited by thiazide diuretics. Parvalbumin (PV), a Ca(2+)-binding protein that plays a role in muscle fibers and neurons, is selectively expressed in the DCT, where its role remains unknown. We therefore investigated the renal phenotype of PV knockout mice (Pvalb(-/-)) vs. wild-type (Pvalb(+/+)) littermates. PV colocalized with the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC) in the early DCT. The Pvalb(-/-) mice showed increased diuresis and kaliuresis at baseline with higher aldosterone levels and lower lithium clearance. Acute furosemide administration increased diuresis and natriuresis/kaliuresis, but, surprisingly, did not increase calciuria in Pvalb(-/-) mice. NaCl supplementation of Pvalb(-/-) mice increased calciuria at baseline and after furosemide. The Pvalb(-/-) mice showed no significant diuretic response to hydrochlorothiazide, but an accentuated hypocalciuria. A decreased expression of NCC was detected in the early DCT of Pvalb(-/-) kidneys in the absence of ultrastructural and apoptotic changes. The PV-deficient mice had a positive Ca(2+) balance and increased bone mineral density. Studies in mouse DCT cells showed that endogenous NCC expression is Ca(2+)-dependent and can be modulated by the levels of PV expression. These results suggest that PV regulates the expression of NCC by modulating intracellular Ca(2+) signaling in response to ATP in DCT cells. They also provide insights into the Ca(2+)-sparing action of thiazides and the pathophysiology of distal tubulopathies