Pharmacokinetic profile of bisphosphonates in the treatment of metabolic bone disorders

The pharmacokinetic profile of bisphosphonates is complex and depends on their potency in inhibiting bone resorption through their cellular effects and on the physicochemical action related to the interaction of these compounds with bone matrix. Amino-substituted bisphosphonates exert a more potent cellular effect on osteoclast via the inhibition of the mevalonate pathway, whereas non-nitrogen containing compounds exert a weaker effect deriving from the induction of intracellular metabolites in osteoclasts. For nitrogen-containing bisphosphonates there is a correlation between in vitro potency of inhibition of a specific enzyme, farnesyl pyrophosphate synthase, and their antiresorptive potency in vivo. Besides these effects on osteoclasts, bisphosphonates may in part mediate indirectly their antiresoprtive activity through several effects on osteoblasts and osteocytes. Different binding affinities of bisphopshonates to hydroxyapatite depend on both side chains structures and may explain how these drugs reach bone cells and exert their prolonged action in terms of adsorption and desorption processes. Clinical and animalmodels derived data indicate that agents with high anti-resorptive potency, favourable bone binding characteristics and good tolerability can be used with long between-dose intervals to optimize therapeutic outcome

BUM Desa (Village-Owned Enterprises) Accessibility Analysis in Accelerating Village SDGs Achievement

Abstract The accessibility of BUM Desa is related to the development of BUM Desa, which is also one of the driving factors towards achieving the Village SDGs. This research aims to analyse the accessibility of BUM Desa in accelerating the achievement of Village SDGs. The research approach uses quantitative. The results showed that there is a valuable and circumstantial connection between the accessibility of BUM Desa and the development of BUM Desa. In addition, it was obtained that BUM Desa with "Basic" development status has poor accessibility (93.3%), while BUM Desa with "Developing" development status has a better level of accessibility (66.7%). Likewise, BUM Desa with “Advanced” development status has excellent accessibility (60%). The development of BUM Desa is related to the 8th Village SDGs "Equitable Village Economic Growth". To accelerate the achievement of Village SDGs Goals, interventions related to BUM Desa accessibility are needed.   Keywords:Accessibility, BUM Desa, Village SDGs, Bogor Regenc

Safety profile of drugs used in the treatment of osteoporosis: a systematical review of the literature.

The range of osteoporosis treatments is increasingly large and, like any disease, the pharmacological management of patients should involve a risk/benefit evaluation to attain the greatest reduction in risk of fracture with the lowest incidence of adverse events. The aim of this review is to critically appraise the literature about the safety issues of the main pharmacological treatments of osteoporosis. This document is the result of a consensus of experts based on a systematic review of regulatory documents, randomized controlled trials, metaanalyses, pharmacovigilance surveys and case series related to possible adverse drug reactions to osteoporosis treatment with calcium and vitamin D supplements, bisphosphonates, strontium ranelate, selective estrogen receptor modulators, denosumab, and teriparatide. As expected, randomized controlled trials showed only the most common adverse events due to the samples size and the short observation time. Case series and observational studies are able to provide data about uncommon side effects, but in some cases a sure cause-effect relationship needs still to be confirmed. Consistently with methodological limitations, the newer drugs have a tolerance profile that has not been fully explored yet. Osteoporosis treatments showed an overall good tolerance profile with rare serious adverse events that, however, must be well known by the clinician who prescribes these drugs. The concern about possible adverse events should be weighed against the reduction of morbidity and mortality associated with a significant fracture risk reduction

The relationship between educational level and bone mineral density in postmenopausal women

BACKGROUND: This study describes the influence of educational level on bone mineral density (BMD) and investigating the relationship between educational level and bone mineral density in postmenopausal women. METHODS: A total of 569 postmenopausal women, from 45 to 86 years of age (mean age of 60.43 ± 7.19 years) were included in this study. A standardized interview was used at the follow-up visit to obtain information on demographic, life-style, reproductive and menstrual histories such as age at menarche, age at menopause, number of pregnancies, number of abortions, duration of menopause, duration of fertility, and duration of lactation. Patients were separated into four groups according to the level of education, namely no education (Group 1 with 209 patients), elementary (Group 2 with 222 patients), high school (Group 3 with 79 patients), and university (Group 4 with 59 patients). RESULTS: The mean ages of groups were 59.75 ± 7.29, 61.42 ± 7.50, 60.23 ± 7.49, and 58.72 ± 7.46, respectively. Spine BMD was significant lower in Group 1 than that of other groups (p < 0.05). Trochanter and ward's triangle BMD were the highest in Group 4 and there was a significant difference between Group 1 and 4 (p < 0.05). The prevalence of osteoporosis showed an inverse relationship with level of education, ranging from 18.6% for the most educated to 34.4% for the no educated women (p < 0.05). Additionally, there was a significant correlation between educational level and spine BMD (r = 0.20, p < 0.01), trochanter BMD (r = 0.13, p < 0.01), and ward's BMD (r = 0.14, p < 0.01). CONCLUSIONS: The results of the study suggest that there is a significant correlation between educational level and BMD. Losses in BMD for women of lower educational level tend to be relatively high, and losses in spine and femur BMD showed a decrease with increasing educational level

Improvement of pain and regional osteoporotic changes in the foot and ankle by low-dose bisphosphonate therapy for complex regional pain syndrome type I: a case series

<p>Abstract</p> <p>Introduction</p> <p>Complex regional pain syndrome is characterized by pain, allodynia, hyperalgesia, edema, signs of vasomotor instability, movement disorders, joint stiffness, and regional osteopenia. It is recognized to be difficult to treat, despite various methods of treatment, including physiotherapy, calcitonin, corticosteroids, sympathetic blockade, and nonsteroidal anti-inflammatory drugs. Pathophysiologically, complex regional pain syndrome reveals enhanced regional bone resorption and high bone turnover, and so bisphosphonates, which have a potent inhibitory effect on bone resorption, were proposed for the treatment of complex regional pain syndrome.</p> <p>Case presentation</p> <p>A 48-year-old Japanese man with complex regional pain syndrome type I had severe right ankle pain with a visual analog scale score of 59 out of 100 regardless of treatment with physiotherapy and nonsteroidal anti-inflammatory drugs for five months. Radiographs showed marked regional osteoporotic changes and bone scintigraphy revealed a marked increase in radioactivity in his ankle. One month after the start of oral administration of risedronate (2.5 mg per day), his bone pain had fallen from a VAS score of 59 out of 100 to 18 out of 100. Bone scintigraphy at 12 months showed a marked reduction in radioactivity to a level comparable to that in his normal, left ankle. On the basis of these results, the treatment was discontinued at 15 months. At 32 months, our patient had almost no pain and radiographic findings revealed that the regional osteoporotic change had returned to normal.</p> <p>A second 48-year-old Japanese man with complex regional pain syndrome type I had severe right foot pain with a visual analog scale score of 83 out of 100 regardless of treatment with physiotherapy and nonsteroidal anti-inflammatory drugs for nine months. Radiographs showed regional osteoporotic change in his phalanges, metatarsals, and tarsals, and bone scintigraphy revealed a marked increase in radioactivity in his foot. One month after the start of oral administration of alendronate (35 mg per week), his bone pain had fallen from a visual analog scale score of 83 out of 100 to 30 out of 100 and, at nine months, was further reduced to 3 out of 100. The treatment was discontinued at 15 months because of successful pain reduction. At 30 months, our patient had no pain and the radiographic findings revealed marked improvement in regional osteoporotic changes.</p> <p>Conclusions</p> <p>We believe low-dose oral administration of bisphosphonate is worth considering for the treatment of idiopathic complex regional pain syndrome type I accompanied by regional osteoporotic change.</p

Effective Dosage and Administration Schedule of Oral Alendronate for Non-nociceptive Symptoms in Rats with Chronic Constriction Injury

We evaluated the efficacy of oral alendronate with different dosing regimens for non-nociceptive symptoms and osteoporosis in a sciatic nerve chronic constriction injury (CCI) model. Male Sprague-Dawley rats (n=60) were subdivided into sham control (SC) group and CCI groups, which were divided according to dosage and time of oral alendronate administration: no treatment (NT), low dosage early (LE), high dosage early (HE), low dosage late (LL) and high dosage late (HL). We measured the thickness and temperature of the hind paw, bone mineral density (BMD) of the tibia, along with tibia bone strength. On the 14th day post-CCI, the HE group showed significant reduction in thickness and temperature (P<0.001). On the 42nd day post-CCI, the HE group showed significant reduction in temperature compared to the NT group (P<0.001). Also, both HE and HL groups showed statistically significant increased tibia BMD (P<0.001), along with increase of tibia bone strength compared to the NT group. Based on these findings, early alendronate in high dosages is effective in the non-nociceptive symptoms; early and late alendronate in high dosages, are effective in preventing bone dystrophic changes in a CCI model

Use of medications with anticholinergic activity and self-reported injurious falls in older community-dwelling adults

Objectives: To assess the association between the use of medications with anticholinergic activity and the subsequent risk of injurious falls in older adults. Design: Prospective, population-based study using data from The Irish Longitudinal Study on Ageing. Setting: Irish population. Participants: Community-dwelling men and women without dementia aged 65 and older (N = 2,696). Measurements: Self-reported injurious falls reported once approximately 2 years after baseline interview. Self-reported regular medication use at baseline interview. Pharmacy dispensing records from the Irish Health Service Executive Primary Care Reimbursement Service in a subset (n = 1,553). Results: Nine percent of men and 17% of women reported injurious falls. In men, the use of medications with definite anticholinergic activity was associated with greater risk of subsequent injurious falls (adjusted relative risk (aRR) = 2.55, 95% confidence interval (CI) = 1.33-4.88), but the risk of having any fall and the number of falls reported were not significantly greater. Greater anticholinergic burden was associated with greater injurious falls risk. No associations were observed for women. Findings were similar using pharmacy dispensing records. The aRR for medications with definite anticholinergic activity dispensed in the month before baseline and subsequent injurious falls in men was 2.53 (95% CI = 1.15-5.54). Conclusion: The regular use of medications with anticholinergic activity is associated with subsequent injurious falls in older men, although falls were self-reported after a 2-year recall and so may have been underreported. Further research is required to validate this finding in men and to consider the effect of duration and dose of anticholinergic medications

Pain prediction by serum biomarkers of bone turnover in people with knee osteoarthritis: an observational study of TRAcP5b and cathepsin K in OA

Objectives: To investigate serum biomarkers, tartrate resistant acid phosphatase 5b (TRAcP5b) and cathepsin K, indicative of osteoclastic bone resorption, and their relationship to pain and pain change in knee osteoarthritis (OA). Methods: Sera and clinical data were collected from 129 people (97 with 3-year follow-up) with knee OA from the Prediction of Osteoarthritis Progression (POP) cohort. Knee OA-related outcomes in POP included: WOMAC pain, NHANES I (pain, aching and stiffness), subchondral sclerosis, and radiographically determined tibiofemoral and patellofemoral OA. Two putative osteoclast biomarkers were measured in sera: TRAcP5b and cathepsin K. Medial tibia plateaux were donated at knee arthroplasty for symptomatic OA (n=84) or from 16 post mortem controls from the Arthritis Research UK (ARUK) Pain Centre joint tissue repository. Osteoclasts were stained for TRAcP within the subchondral bone of the medial tibia plateaux. Results: Serum TRAcP5b activity, but not cathepsin K-immunoreactivity, was associated with density of TRAcP-positive osteoclasts in the subchondral bone of medial tibia plateaux. TRAcP-positive osteoclasts were more abundant in people with symptomatic OA compared to controls. Serum TRAcP5b activity was associated with baseline pain and pain change. Conclusions: Our observations support a role for subchondral osteoclast activity in the generation of OA pain. Serum TRAcP5b might be a clinically relevant biomarker of disease activity in OA