New drug form stabilized form of human calcitonin may help treat osteoporosis

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A novel form of a drug used to treat osteoporosis that comes with the potential for fewer side effects may provide a new option for patients.

The work is supported by the National Institutes of Health and is published in Biophysical Journal.

Purdue University innovators developed a stabilized form of human calcitonin, which is a peptide drug already used for people with osteoporosis. Researchers at Purdue created a prodrug form of the peptide hormone to increase its effectiveness as an osteoporosis treatment.

In humans, calcitonin is the hormone responsible for normal calcium homeostasis.

When prescribed to osteoporosis patients, calcitonin inhibits bone resorption, resulting in increased bone mass.

Unfortunately, human calcitonin undergoes fibrillation in aqueous solution, leading to reduced efficacy when used as a therapeutic. As a substitute, osteoporosis patients are prescribed salmon calcitonin. It does not fibrillate as rapidly but suffers from low potency and the potential for several adverse side effects.

“The technology can help make these calcitonin drugs safer and more effective,” said Elizabeth Topp, a Purdue professor of physical and industrial pharmacy.

“Our approach will increase the therapeutic potential of human calcitonin, promising a more effective option to replace salmon calcitonin for osteoporosis and related disorders.”

To decrease the fibrillation propensity and increase the therapeutic benefit of human calcitonin, Purdue researchers phosphorylated specific amino acid residues.

“Many promising new peptide drugs tend to form fibrils,” Topp said. “This technology provides a way to stabilize them in a reversible way so that the stabilizing modification comes off when the drug is given to the patient.”


lucocorticoids are widely used in a variety of diseases, especially autoimmune diseases and inflammatory diseases, such as rheumatoid arthritis, nephrotic syndrome, systemic lupus erythematosus, inflammatory bowel disease and severe infection and shock. Nearly 1–2% of the world’s people take GCs for a long time, and up to 30–40% of them may have a history of fragile fractures [1], especially the TH, LS and femoral neck fractures [2].

The duration and dose of glucocorticoids can have a serious impact on the risk of fracture. Among the patients who used GCs for a long time, the incidence of fracture (5%) was twice as high as that of those who used GCs for a short time (2.5%) [3]. In addition, the higher the dose, the higher the incidence of fracture. Taking 2.5 mg of prednisone per day will increase the risk of fracture. If the dose is more than 7.5 mg, the risk of fracture will increase as much as 5 times [4].

There are mainly three kinds of anti-osteoporosis drugs: (1) Anti-bone resorption drugs include bisphosphates (such as alendronate, zoledronic acid, risedronate, ibandronate, etidronate and clodronate, etc.), calcitonin (such as elcatonin and salcatonin), selective estrogen receptor modulators (SERMs) (such as raloxifene) and cathepsin K inhibitors. (2)

Drugs that promote bone formation include parathyroid hormone analogue (PTHa) (such as teriparatide), active vitamin D and its analogues (such as alfacalcidol and calcitriol); (3) double-acting drugs including strontium salts (such as strontium ranelate) and receptor activator of nuclear factor kappaB ligand (RANKL) inhibitors (such as denosumab).

This study will systematically compare the effectiveness and safety of the above-mentioned drugs.

Bisphosphonate is currently the most widely used anti-osteoporosis drug. As an analog of pyrophosphate, it has a strong affinity for hydroxyapatite and can be selectively absorbed and adhered to the mineral surface of bones, resulting in osteoclasts apoptosis, thus exerting an anti-bone resorption effect [5].

Calcitonin drugs mainly reduce bone resorption by inhibiting the number and secretion activity of osteoclasts. Its efficacy is 40–50 times that of human calcitonin, and it can take effect quickly within 2 hours [6].

SERMs play different roles in different tissues. For example, raloxifene can play an estrogen-like effect after binding to the receptor in bone tissue: inhibit bone resorption, increase bone density, and reduce fracture incidence. In the uterus or breast tissue, it presents an estrogen antagonistic effect: inhibits the proliferation of breast and endometrium.

As a PTHa that promotes bone formation, teriparatide can enhance osteoblast activity, promote bone formation, increase bone mineral density, improve bone quality, and reduce the risk of vertebral and non-vertebral fractures [7].

Representative drugs of active vitamin D and its analogues are 1α-hydroxyvitamin D3 (alfacalcidol) and 1,25 (OH)2 -VD3 (calcitriol). They are more suitable for the elderly, patients with osteoporosis complicated with renal insufficiency and with 1α hydroxylase deficiency or reduction, which can increase bone density, reduce falls, and the incidence of fractures [8].

As an inhibitor of nuclear factor kappa-B receptor activating factor ligand (RANKL), denosumab can inhibit the binding of RANKL to its receptor and reduce the formation, function and survival of osteoclasts, thus reducing bone resorption, increasing bone mass and improving the strength of cortical or cancellous bone [9].

The above-mentioned different types of drugs have different mechanisms of action. Generally speaking, they can be summarized as anti-bone resorption and promoting bone formation. However, there are few studies that can comprehensively compare these drugs. This article compares their efficacy and safety through a NMA, which provides more valuable suggestions for clinical medication.

Discussion

We conducted a NMA of different types of anti-osteoporosis drugs and reached the following conclusions: Among the different types of anti-osteoporosis drugs, teriparatide (SUCRA 95.9%) has the best effect in reducing the incidence of vertebral fractures; ibandronate (SUCRA 75.2%) has the best effect in reducing the incidence of non-vertebral fractures; raloxifene (SUCRA 98.5%) has the best effect in increasing LS BMD; denosumab (SUCRA 99.7%) is the best in increasing TH BMD; calcitonin (SUCRA 92.4%) has the lowest incidence of adverse events.

We obtained the following results through NMA of different kinds of anti-osteoporotic drugs. Compared with placebo, the incidence of vertebral fracture was very low in teriparatide (RR0.06, 95%CI 0.01–0.27) and etidronate (RR0.29, 95%CI 0.16–0.51); raloxifene (SMD12.56, 95%CI 6.33–18.78) and pamidronate (SMD 6.84, 95%CI 2.26–11.42) significantly increased LS BMD; denosumab (SMD12.63, 95%CI 6.51–18.75) and pamidronate (SMD5.14, 95%CI 3.15–8.94) increased BMD of the TH. There were no significant differences in the incidence of nonvertebral fractures or adverse effects of the other drugs compared with placebo.

Previous NMA showed that teriparatide was the most effective anti-osteoporotic drug for vertebral fractures [61–66] and the lowest incidence of ibandronate for non-vertebral fractures [61,63]. These two conclusions are consistent with this study. For the increase of LS BMD, the results of, M. A. Amiche et al. [61] show that ibandronate is the best, while this paper found that raloxifene is the best, we should be cautious about the differences in these results.

In addition, our analysis shows that vitamin D analogues (such as calcitriol) and active metabolites (such as alfacalcidol) may be more effective in preventing fractures than vitamin D alone. This provides an evidence-based medicine basis for clinical drug use in the future. Vitamin D should not be used only, but its analogues and active metabolites should be used in combination.

Although the efficacy of the above anti-osteoporotic drugs is significant, their adverse reactions cannot be ignored at the same time. As one of the representative drugs of bisphosphate, the main adverse events of ibandronate are gastrointestinal reactions, including epigastric pain, acid regurgitation, inflammation of the esophagus and stomach and so on.

Other adverse reactions include affecting renal function, so patients with GFR less than 35 mL/min should disable ibandronate. In addition, the lower incidence of adverse events included osteonecrosis of the jaw and atypical femur fracture [67]. A randomized controlled trial showed that adverse events to teriparatide included nausea (18%), headaches (13%) and leg cramps (3%) [7].

The main adverse reactions of denosumab are infections, such as urinary tract infection, sinusitis, pharyngitis, bronchitis and cellulitis. Others include joint pain and hypocalcemia [68]. Raloxifene is well tolerated, the side effects are limited to hot flashes and vaginal dryness, and the risk of thromboembolism is slightly increased [69]. Intranasal calcitonin can cause rhinitis, nosebleeds and allergic reactions, especially in people with a history of salmon allergy [70].

This article has the following advantages. First, this article is to study the most complete mesh meta-analysis of anti-osteoporosis drugs. Second, this article is an earlier study of an NMA of anti-osteoporosis drugs on the BMD of the LS and TH. Third, this article first includes several drugs that have not been studied in previous NMA, including calcitonin, clodronate, sodium fluoride, eldecalcitol, monofluorophosphate, and mineralronate.

However, there are some shortcomings in our research. First, the menopause of female subjects may affect the efficacy of the drug. Second, the patients included in this study were given long-term calcium and vitamin D supplementation, which also had an impact on the efficacy of the drug.

Third, the research time of the articles included in this paper varies greatly, from 12 months to 36 months, or even longer. Fourth, the number of randomized controlled trials for direct comparison of some drugs included in this paper is relatively small, which leads to the fact that the results of indirect comparison may not be very persuasive and should be treated with caution. Last, this paper includes the original research of different countries and regions, which is also one of the limitations of this paper. Therefore, more experiments are needed to verify or correct the results of this paper.

reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743932/


More information: Harshil K. Renawala et al, Fibrillation of Human Calcitonin and Its Analogs: Effects of Phosphorylation and Disulfide Reduction, Biophysical Journal (2020). DOI: 10.1016/j.bpj.2020.11.009

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