Use of Teriparatide to improve fracture healing: What is the evidence?

Teriparatide is a recombinant form of the biologically active component of Parathyroid hormone. It has been shown to increase bone mass and prevent fractures in osteoporotic bone. It is licensed by the Food and Drug Administration for the treatment of Osteoporosis. Over the last decade, a growing body of evidence has accumulated suggesting a role for Teriparatide in the management of fractures. Studies in both normal and delayed healing models have shown improvement in callus volume and mineralisation, bone mineral content, rate of successful union and strength at fracture sites. However most of these results have been derived from animal studies. The majority of this research on humans has comprised low level evidence, with few randomised controlled trials, many case reports and case series. Nevertheless, the results from these studies seem to support research from animal models. This has led to a growing number of clinicians using Teriparatide “off license” to treat fractures and non-unions in their patients. This review presents a critical appraisal of the current evidence supporting the use of Teriparatide for fracture healing, delayed unions and non unions and in the setting of osteoporotic fractures, the studies producing this evidence and their transferability to human beings.     

Effects of palmitoylation of Cys(415) in helix 8 of the CB(1) cannabinoid receptor on membrane localization and signalling

BACKGROUND AND PURPOSE

The CB₁ cannabinoid receptor is regulated by its association with membrane microdomains such as lipid rafts. Here, we investigated the role of palmitoylation of the CB₁ receptor by analysing the functional consequences of site-specific mutation of Cys⁴¹⁵, the likely site of palmitoylation at the end of helix 8, in terms of membrane association, raft targeting and signalling.

EXPERIMENTAL APPROACH

The palmitoylation state of CB₁ receptors in rat forebrain was assessed by depalmitoylation/repalmitoylation experiments. Cys⁴¹⁵ was replaced with alanine by site-directed mutagenesis. Green fluorescence protein chimeras of both wild-type and mutant receptors were transiently expressed and functionally characterized in SH-SY5Y cells and HEK-293 cells by means of confocal microscopy, cytofluorimetry and competitive binding assays. Confocal fluorescence recovery after photobleaching was used to assess receptor membrane dynamics, whereas signalling activity was assessed by [³⁵S]GTPγS, cAMP and co-immunoprecipitation assays.

KEY RESULTS

Endogenous CB₁ receptors in rat brain were palmitoylated. Mutation of Cys⁴¹⁵ prevented the palmitoylation of the receptor in transfected cells and reduced its recruitment to plasma membrane and lipid rafts; it also increased protein diffusional mobility. The same mutation markedly reduced the functional coupling of CB₁ receptors with G-proteins and adenylyl cyclase, whereas depalmitoylation abolished receptor association with a specific subset of G-proteins.

CONCLUSIONS AND IMPLICATIONS

CB₁ receptors were post-translationally modified by palmitoylation. Mutation of Cys⁴¹⁵ provides a receptor that is functionally impaired in terms of membrane targeting and signalling.

LINKED ARTICLES

This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7     

The cost-effectiveness of a competitive voucher scheme to reduce sexually transmitted infections in high-risk groups in Nicaragua

Current evidence suggests that sexually transmitted infection (STI) interventions can be an effective means of human immunodeficiency virus (HIV) prevention in populations at an early stage of the epidemic. However, evidence as to their cost-effectiveness when targeted at high-risk groups is lacking. This paper assesses the cost-effectiveness of a competitive voucher scheme in Managua, Nicaragua aimed at high-risk groups, who could redeem the vouchers in exchange for free STI testing and treatment, health education and condoms, compared with the status quo (no scheme). A provider perspective was adopted, defined as: the voucher agency and health care providers from the public, NGO and private sectors. The cost of the voucher scheme was estimated for a 1-year period (1999) from project accounts using the ingredients approach. Outcomes were monitored as part of ongoing project evaluation. Costs and outcomes in the absence of the scheme were modelled using project baseline data and reports, and relevant literature. The annual cost of providing comprehensive STI services through vouchers was US$62 495, compared with an estimated US$17 112 for regular service provision in the absence of the scheme. 4815 vouchers were distributed by the voucher scheme, 1543 patients were tested for STIs and 528 STIs were effectively cured in this period. In the absence of the scheme, only an estimated 85 cases would have been cured from 1396 consultations. The average cost of the voucher scheme per patient treated was US$41 and US$118 per STI effectively cured, compared with US$12 per patient treated and US$200 per STI cured in its absence. The incremental cost of curing an STI through the voucher scheme, compared with the status quo, was US$103. A voucher scheme offers an effective and efficient means of targeting and effectively curing STIs in high-risk groups, as well as encouraging quality care practices.     

Beyond health gain: the range of health system benefits expressed by social groups in Mexico and Central America

Current health reform proposals in most developing countries stress health gain as the chief evaluation criterion. Essential service packages are formulated using cost-effectiveness methods for the selection of interventions without sufficient regard for other factors that are significant for successful implementation and acceptance by the needy. This paper presents the results of research undertaken in Mexico and Central America to test the hypothesis that population groups view health gain as only one among several benefits derived from health systems. The goal at this stage was two-fold: (a) to identify through qualitative methods the range of benefits that are significant for a wide cross-section of social groups and (b) to classify such benefits in types amenable to be used in the development of instruments to measure the benefits intended and actually produced by health systems. Fourteen focus groups were undertaken in Costa Rica, El Salvador, Guatemala, Mexico and Nicaragua representing diverse age, gender, occupation and social conditions. Six major types of health system benefits were identified besides health gain: reassurance/uncertainty reduction, economic security, confidence in health system quality, financial benefits derived from the system, health care process utility and health system fairness. Benefits most often mentioned can be classed under health care process utility and confidence in system quality. They also have the most consensus across social groups. Other benefits mentioned have an affinity with social conditions. Human resource-derived utility stands out by its frequency in the range of benefits mentioned. Health systems and health sector reform proposals must emphasise those aspects of quality related to human resources to be in accord with population expectations.