The effect of vitamin D plus protein supplementation on sarcopenia: A systematic review and meta-analysis of randomized controlled trials.

PURPOSE: The exact effect of vitamin D supplementation, either as monotherapy or in combination with protein, on musculoskeletal health in patients with sarcopenia is currently unknown. This study aimed to determine the effect of vitamin D alone or with protein supplementation on muscle strength, mass, and performance in this population. METHODS: A comprehensive search was conducted in Medline, Cochrane Central and Scopus databases, up to March 31st, 2020. Data were expressed as standardized mean difference (SMD) with 95 % confidence intervals (CI). I2 index was employed for heterogeneity. RESULTS: The initial search identified 1164 studies, eight of which met the eligibility criteria for qualitative and quantitative analysis, yielding a total of 776 patients. Vitamin D (100-1600 IU/day) plus protein (10-44 g/day) supplementation exhibited a beneficial effect on muscle strength, as demonstrated by an improvement in handgrip strength (SMD 0.38 ± 0.07, 95 % CI 0.18-0.47, p = 0.04; I2 76.2 %) and a decrease in the sit-to-stand time (SMD 0.25 ± 0.09, 95 % CI 0.06-0.43, p = 0.007; I2 0%) compared with placebo. However, the effect on muscle mass, assessed by skeletal muscle index, was marginally non-significant (SMD 0.25 ± 0.13, 95 % CI -0.006-0.51, p = 0.05; I2 0%). No effect on appendicular skeletal muscle mass or muscle performance (assessed by walking speed) was observed with vitamin D plus protein. CONCLUSIONS: Vitamin D supplementation, combined with protein, improves muscle strength in patients with sarcopenia, but has no effect on muscle mass or performance.

Limb-salvage surgery offers better five-year survival rate than amputation in patients with limb osteosarcoma treated with neoadjuvant chemotherapy. A systematic review and meta-analysis.

BACKGROUND: Osteosarcoma is the most common primary bone sarcoma. Currently, the main treatment option for high-grade osteosarcomas is neoadjuvant chemotherapy, followed by surgical resection of the lesion and adjuvant chemotherapy. Limb salvage surgery (LSS) and amputation are the main surgical techniques; however, controversy still exists concerning the best surgical method. Our meta-analysis compared the effectiveness of LSS and amputation combined with neoadjuvant chemotherapy in patients with limb osteosarcoma, in terms of 5-year overall survival (OS), 5-year disease-free survival (DFS) and local recurrence rate. METHODS: Following the established methodology of PRISMA guidelines, a literature search was conducted in PubMed, Cochrane, Google Scholar from 1975 until January 2020. Two independent reviewers evaluated the study quality based on the Newcastle-Ottawa scale. Odds ratio and 95% confidence interval of the OS, DFS and local recurrence rate were calculated. RESULTS: Thirteen studies were finally included with a total of 2884 patients; 1986 patients undergone LSS and 898 amputations. Five-year overall survival was almost 2-fold in patients treated with LSS than those treated with amputation (OR: 1.99; 95% CI: 1.35-2.93; I2 = 74%, p < 0.001). No difference was found in 5-year DFS between LSS patients and amputees (OR: 1.24; 95% CI: 0.55-2.79; I2 = 67%, p = 0.01). The odds of local recurrence was numerically higher in LSS compared to amputation but not statistically significant (OR: 2.29; 95% CI: 0.95-5.53; I2 = 47%, p = 0.05). However, the included studies did not clearly define differences in the stages of patients of the two groups. CONCLUSION: Our study demonstrated that in patients with limb osteosarcoma treated with neoadjuvant chemotherapy, LSS is associated with a higher 5-year overall survival and the odds of local recurrence may be increased but these results should be interpreted with caution due to high heterogeneity.

Vitamin D supplementation and fracture risk: Evidence for a U-shaped effect.

During the last decade, a cascade of evidence has questioned the anti-fracture efficacy of vitamin D supplementation. In general, vitamin D status, reflected by serum 25-hydroxy-vitamin D [25(OH)D] concentrations, seems to predict fracture risk and bone mineral density (BMD). Despite the well-documented detrimental effect of vitamin D deficiency on bones, vitamin D monotherapy does not seem to reduce the risk of fractures. On the other hand, high vitamin D doses, either at monthly (60,000-100,000 IU) or daily intervals (>4000 IU), appear to be harmful with regard to falls, fracture risk and BMD, especially for people without vitamin D deficiency and at low fracture risk. Therefore, a U-shaped effect of vitamin D on the musculoskeletal system may be supported by the current evidence. Vitamin D supplementation could be of value, at daily doses of at least 800 IU, co-supplemented with calcium (1000-1200  mg/day), in elderly populations, especially those with severe vitamin D deficiency [25(OH)D <25-30  nmol/L (<10-12  ng/mL)], although its anti-fracture and anti-fall efficacy is modest. Good compliance and at least 3-5 years of therapy are required.

Current and emerging osteoporosis pharmacotherapy for women: state of the art therapies for preventing bone loss.

INTRODUCTION: Pharmacological options to address the imbalance between bone resorption and accrual in osteoporosis include anti-resorptive and osteoanabolic agents. Unique biologic pathways such as the Wnt/ß-catenin pathway have been targeted in the quest for new emerging therapeutic strategies. AREAS COVERED: This review provides an overview of existing pharmacotherapy for osteoporosis in women and explore state-of-the-art and emerging therapies to prevent bone loss, with an emphasis on the mechanism of action, indications and side effects. EXPERT OPINION: Bisphosphonates appear to be a reliable and cost-effective option, whereas denosumab has introduced a simpler dosing regimen and may achieve a linear increase in bone mineral density (BMD) with no plateau being observed, along with continuous anti-fracture efficacy. Abaloparatide, a parathyroid-hormone-related peptide (PTHrP)-analogue, approved by the FDA in April 2017, constitutes the first new anabolic osteoporosis drug in the US for nearly 15 years and has also proven its anti-fracture efficacy. Romosozumab, a sclerostin inhibitor, which induces bone formation and suppresses bone resorption, has also been developed and shown a significant reduction in fracture incidence; however, concerns have arisen with regard to increased cardiovascular risk.

Inducible nitric oxide synthase as a target for osteoarthritis treatment.

INTRODUCTION: Inducible nitric oxide synthase (iNOS) is the enzyme responsible for the production of nitric oxide (NO), a major proinflammatory and destructive mediator in osteoarthritis (OA). Areas covered: This is a comprehensive review of the recent literature on the involvement of iNOS in osteoarthritis and its potential to be used as a target for OA treatment. Evidence from in vitro, in vivo and human studies was systematically collected using medical search engines. Preclinical studies have focused on the effect of direct and indirect iNOS inhibitors in both animal and human tissues. Apart from direct inhibitors, common pharmacological agents, herbal and dietary medicines as well as hyperbaric oxygen, low level laser and low intensity pulsed ultrasound have been shown to exhibit a chondroprotective effect by inhibiting the expression of iNOS. Expert opinion: Data support the further investigation of iNOS inhibitors for the treatment of OA in human studies and clinical trials. Indirect iNOS inhibitors such as interleukin 1 inhibitors also need to be studied in greater detail. Finally, human studies need to be conducted on the herbal and dietary medicines and on the non-invasive, non-pharmacological treatments.

Management of glucocorticoid-induced osteoporosis: clinical data in relation to disease demographics, bone mineral density and fracture risk.

INTRODUCTION: Glucocorticoid-induced osteoporosis (GIOP) is the most common type of secondary osteoporosis. Patient selection and the treatment choice remain to be controversial. None of the proposed management guidelines are widely accepted. We evaluate the available clinical data, the efficacy of current medication and we propose an overall algorithm for managing GIOP. AREAS COVERED: This article provides a critical review of in vivo and clinical evidence regarding GIOP and developing evidence-based algorithm of treatment. Data base used includes MEDLINE® (1950 to May 2014). EXPERT OPINION: Patient-specific treatment is the gold standard of care. Glucocorticoid (GC)-treated patients must comply with a healthy lifestyle and receive 1000 mg of calcium and at least 800 mg of Vitamin D daily. Bisphosphonate (BP) therapy is the current standard of care for prevention and treatment of GIOP. Most of bisphosphonates demonstrated benefit in lumbar bone mineral density (BMD) and some in hip BMD. Alendronate, risedronate and zoledronate showed vertebral anti-fracture efficacy in postmenopausal women and men. Scarce data however when compared head to head with BP efficacy. In post-menopausal women, early antiresorptive BP treatment appears to be efficient and safe. In premenopausal women and patients at high risk of fracture receiving long-term GC therapy however, teriparitide may be advised alternatively.

Investigating the role of PDGF as a potential drug therapy in bone formation and fracture healing.

BACKGROUND: Platelet-derived growth factor (PDGF) has been shown in vivo to increase bone formation and supplement fracture healing, and may have a role as a therapeutic agent in the treatment of bone loss and fracture healing in humans. OBJECTIVE: A comprehensive review of the recent literature on the effect of PDGF on bone mineral density and fracture healing. METHODS: In vitro and in vivo evidence was systematically collected using medical search engines MEDLINE/OVID (1950 to March 2008) and EMBASE (1980 to March 2008) databases. RESULTS/CONCLUSION: Evidence to date suggests that PDGF-BB, and to a lesser extent PDGF-AA, may have potential therapeutic use in the treatment of osteoporosis and bone healing in humans. Additionally, by targeting alpha-receptors on osteoblasts, a potential anabolic effect on bone metabolism in humans can be anticipated; however, more research needs to be done to assess the role of beta-receptors in human bone.

The potential adverse effects of aromatase inhibitors on wound healing: in vitro and in vivo evidence.

BACKGROUND: Estrogens and several other endogenous substances are recognised as being important in the process of wound healing. However, the effect of aromatase and aromatase inhibition in the wound healing process has yet to be fully defined. OBJECTIVE: A review of the in vitro and in vivo evidence on the effect of aromatase inhibition on wound healing. METHODS: The primary medical search engines used for the study were Ovid MEDLINE (1950 - March 2009) and EMBASE (1980 - March 2009) databases. RESULTS/CONCLUSION: The delayed healing of cutaneous wounds in aged individuals may in part reflect the decline in circulating levels of dehydroepiandrosterone (DHEA) and estrogens. The beneficial response on wound healing that DHEA and estrogen exert may be blocked by aromatase inhibition. Based on animal models, aromatase inhibitors may adversely affect cutaneous wound healing in the acute setting. So far, there have been no clinical trials investigating the adverse affect of aromatase inhibitors on the process of cutaneous wound healing in humans. Postmenopausal patients who take aromatase inhibitors as an adjunct to breast cancer therapy may, therefore, be at increased risk of delayed wound healing. Further studies are necessary to assess the extent of the effects on the wound healing process.

The effect of beta-blockers on bone metabolism as potential drugs under investigation for osteoporosis and fracture healing.

BACKGROUND: beta-Adrenergic receptor antagonists (beta-blockers) have a well-recognised antihypertensive action that is mediated through a reduction in cardiac output and in the release of renin from the kidneys and inhibition of the action of endogenous catecholamines on beta-adrenergic receptors. This class of drugs has been shown to reduce the incidence of cardiovascular disease. Recent evidence suggests that beta-blockers may also have an effect on bone structure, metabolism and fracture healing. OBJECTIVE: This paper reviews in vitro and in vivo data that suggest beta-blockers have primarily an anabolic effect on bone metabolism. RESULTS: The sympathetic nervous system has a catabolic effect on bone, and in vitro studies have shown that adrenergic agonists stimulate bone resorption. The beta-blocker propranolol has been shown to increase bone formation in ovariectomised female rats. Also, recent observational clinical studies provide evidence to show that beta-blockers are associated with reduction in fracture risk in both men and women. CONCLUSION: Although there are some controversial studies, most research concludes that beta-blockers show promise in the treatment of osteoporosis and fracture healing.

Enhancement of fracture healing with parathyroid hormone: preclinical studies and potential clinical applications.

Parathyroid hormone (PTH) has become the most widely studied hormone with regard to its administration to various species and their respective skeletal responses. Beyond its affirmative effect in osteoporosis treatment, systemic PTH administration seems to stimulate bone formation in the fracture healing process. According to preclinical experimental studies, once-daily administration of PTH enhances the morphometric and mechanical properties of fracture calluses and accelerates the normal fracture healing. Its anabolic effect is obvious even in low doses, as well as in cases of implant fixation and distraction osteogenesis. There is little evidence of toxic effects and there are only a few reports of adverse events related to its use. The incidence of bone neoplasms in animal studies depends on the dose and duration of treatment. However, it is not prognostic of an equivalent risk potential of carcinogenesis in humans. In summary, the clinical promise of parathyroid hormone is very high and a positive effect in fracture healing should be anticipated.