Adverse Effects of Bisphosphonates: Implications for Osteoporosis Management

Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN 55905, USA.
Mayo Clinic Proceedings (Impact Factor: 6.26). 08/2009; 84(7):632-7; quiz 638. DOI: 10.1016/S0025-6196(11)60752-0
Source: PubMed


Bisphosphonates are widely prescribed and highly effective at limiting the bone loss that occurs in many disorders characterized by increased osteoclast-mediated bone resorption, including senile osteoporosis in both men and women, glucocorticoid-associated osteoporosis, and malignancies metastatic to bone. Although they are generally well tolerated, potential adverse effects may limit bisphosphonate use in some patients. Optimal use of bisphosphonates for osteoporosis requires adequate calcium and vitamin D intake before and during therapy. The World Health Organization fracture risk assessment algorithm is currently available to determine absolute fracture risk in patients with low bone mass and is a useful tool for clinicians in identifying patients most likely to benefit from pharmacological intervention to limit fracture risk. This fracture risk estimate may facilitate shared decision making, especially when patients are wary of the rare but serious adverse effects that have recently been described for this class of drugs.

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    • "It is rarely, that bisphosphonates can cause serious ocular side effects such as ocular inflammation and ocular pain [60] [61], but high risk of this side effects can occur with intravenous administration more than with the oral medication [61] [62]. Other adverse effects that have been associated with the use of bisphosphonates including severe musculoskeletal pain, hypocalcaemia, secondary hyperparathyroidism [63], sever over suppression of bone turnover [53], sub trochanteric femoral fractures [55] [64] and renal frailer associated with zoledronic acid [57]. "
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    ABSTRACT: Osteoporosis is a progressive bone disease that is characterized by a decrease in bone mass and density and deterioration of bone structure which can lead to bone fragility which might increase the risk of fracture. Fractures can be prevented by using osteoporosis drugs. This will save society from accommodation expenses in the hospital, nursing homes and save patients from the loss of quality of life and premature death. Various therapies are available for osteoporosis. The most common are bisphosphonates, raloxifene, calcitonin, teriparatide and denosumab. Bisphosphonates are a widely utilized class of drugs used in the management of disorders of calcium and bone metabolism. The major disadvantage concerning clinical use of bisphosphonate drugs is their poor and variable absorption after oral administration. Therefore, several strategies have been developed to increase their intestinal absorption either by changing the permeability properties of the intestinal absorptive cells or by modifying the structure of the drug through altering the physicochemical properties of the drug itself. Raloxifene is the only selective estrogen receptor modulator that was approved worldwide for the prevention and treatment of postmenopausal osteoporosis, but its low bioavailability limited its use. It has been well established that calcitonin when administered by parental or intranasal routes are effective in preventing postmenopausal bone loss. Recently, oral formulation of calcitonin has been developed to enhance its clinical usefulness and many attempts have been made to enhance its oral bioavailability. The recombinant human parathyroid hormone fragment, rhPTH(1-34) (teriparatide), is a potent anabolic agent used in the treatment of postmenopausal with severe osteoporosis, as well as for persons with established glucocorticoid-induced osteoporosis who are receiving long term glucocorticoids. Teriparatide was shown to reduce fracture risk and is now available for the treatment of patients with osteoporosis who are at high risk of fracture due to its ability to stimulate osteoblast activity to a greater extent than osteoclast. Denosumab offers an alternative approach for the treatment of osteoporosis by decreasing bone resorption and increasing bone mineral density through the inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL).
    Commonly Used Drugs - Uses, Side Effects, Bioavailability & Approaches to Improve it, 1 edited by Rafik Karaman, 01/2015: chapter 7: pages 219-247; Nova Science Publishers., ISBN: 978-1-63463-828-9
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    • "The pharmacological effect of some antiresorptive agents has been studied in healthy adult horses, such as gallium nitrate (Pollina et al., 2012), tiludronate (Delguste et al., 2007), and zoledronate (Nieto et al., 2013). Unlike members of bisphosphonate antiresorptive drugs (e.g., tiludronate and zoledronate) which led to oversuppression of bone turnover (Odvina et al., 2005; Kennel & Drake, 2009), VEL-0230 was found to induce a rapid, short-acting inhibitory effect of bone resorption as proven by efficacy studies in humans, nonhuman primates, dogs, and rats (unpublished data, Asagiri et al., 2008). Studies reported by Asagiri et al. (2008) demonstrated that Cathepsin K sits at the nexus of both musculoskeletal system (bone) and immune system. "
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    ABSTRACT: Plasma pharmacokinetic (PK) and bone resorption biomarker [carboxy-terminal cross-linking telopeptide of type I collagen (CTX-1)] analyses were performed following single and multiple oral dose protocols of a Cathepsin K inhibitor (VEL-0230) in horses. Outcomes included plasma and urine drug and CTX-1 concentrations. In the dose range study, 2, 4, and 8 mg/kg body weight (b.w.) doses were administered in a Latin square design to three mares and evaluated for 1 week. Based on the PK characteristics of VEL-0230, 4 mg/kg b.w. was selected for the dose interval study in which 3.25 days (d) and 7 days dose intervals were evaluated over three administrations using four exercising horses in a Latin square design. The 3.25 days and 7 days dose intervals provided a rapid inhibition of bone resorption based on plasma CTX-1. CTX-1 inhibition prior to next dose administration was not different from baseline in the 3.25 days and 7 days protocols, and for the first 3 days but the sustained CTX-1 inhibition in the 7 days protocol along with the cost and logistic benefits for weekly administration made the 7 days protocol preferable. Weekly administration of VEL-0230 may provide effective inhibition of bone resorption in young exercising horses that returns to baseline within 7 days after drug withdrawal even after multiple doses.
    Journal of Veterinary Pharmacology and Therapeutics 04/2014; 37(6). DOI:10.1111/jvp.12131 · 1.19 Impact Factor
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    • "Bisphosphonates, including alendronate (ALN), efficiently prevent bone loss; however, they have various adverse effects including upset stomach, inflammation of the esophagus, and osteonecrosis of the jaw [3]–[5]. In addition, bisphosphonates also elevate the risk of bone fractures caused by accumulation of microfractures [6]. Another class of anti-resorptive drugs includes estrogens and selective estrogen receptor modulators (SERMs). "
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    ABSTRACT: The Wnt/β-catenin pathway is a potential target for development of anabolic agents to treat osteoporosis because of its role in osteoblast differentiation and bone formation. However, there is no clinically available anti-osteoporosis drug that targets this Wnt/β-catenin pathway. In this study, we screened a library of aqueous extracts of 350 plants and identified Hovenia dulcis Thunb (HDT) extract as a Wnt/β-catenin pathway activator. HDT extract induced osteogenic differentiation of calvarial osteoblasts without cytotoxicity. In addition, HDT extract increased femoral bone mass without inducing significant weight changes in normal mice. In addition, thickness and area of femoral cortical bone were also significantly increased by the HDT extract. Methyl vanillate (MV), one of the ingredients in HDT, also activated the Wnt/β-catenin pathway and induced osteoblast differentiation in vitro. MV rescued trabecular or cortical femoral bone loss in the ovariectomized mice without inducing any significant weight changes or abnormality in liver tissue when administrated orally. Thus, natural HDT extract and its ingredient MV are potential anabolic agents for treating osteoporosis.
    PLoS ONE 01/2014; 9(1):e85546. DOI:10.1371/journal.pone.0085546 · 3.23 Impact Factor
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