Table 2.
Summarizes important data over pharmacological agents used for osteoporosis.
| Category | Summary | |
|---|---|---|
| 1. Antiresorptive Agents | ||
| 1a. Bisphosphonates | ||
| Examples: Alendronate and risedronate (orally), ibandronate (orally or intravenously), Pamidronate (intravenously) and zoledronic acid (intravenously). Usually, the 1st line in management |
Mechanism of action | The antiresorptive effect of bisphosphonates is derived from the affinity for hydroxyapatite and their inhibitory capability to the osteoclast enzyme farnesyl pyrophosphate synthase [98]. They promote apoptosis of osteoclasts resulting in the inhibition of bone resorption and an increase in BMD. |
| Evidence of efficacy | In postmenopausal osteoporosis, these agents improve BMD at the spine (risk reduction 4–9%) and hip (2–6%) after 3 years [99] and decreased fracture risk in comparison with placebo [100]. They also improve BMD in cohorts of Crohn’s patients [101]. A critical issue is that only 1–3% of bisphosphonates are absorbed. In celiac disease, this might be lower, indicating that oral bisphosphonates might be ineffective in active celiac disease versus those in remission. Bone markers, such as CTX (bone resorption) and P1NP (bone formation) should be decreased by 30% or more after 3–6 months of therapy, a high level may indicate poor absorption. In those with poor response, switching to intravenous bisphosphonate is indicated. |
|
| Important side effects/drawbacks | Adverse events of bisphosphonates are uncommon. Oral administration of bisphosphonates may be associated with dysphagia, abdominal pain, nausea, constipation or diarrhea, acid regurgitation, taste distortion, gastritis and esophageal ulcers. Hypocalcemia is reported particularly after starting potent intravenous bisphosphonates such as zoledronic acid. It is strongly recommended to commence the substitution of calcium and vitamin D 2–4 weeks before bisphosphonates to ameliorate the risk of tetany [102]. The incidence of osteonecrosis of the jaw (ONJ) is small in patients using bisphosphonates for osteoporosis prevention or treatment, ranging from less than 1–28 cases per 100,000 person-years of treatment [103]. In cancer patients, a study showed that ONJ developed in 1.4% of those who were treated initially with zoledronic acid, over the course of 5 years [104]. |
|
| 1b. Monoclonal antibodies | ||
| Denosumab 1st or 2nd line in management |
Mechanism of action | It is the most powerful antiresorptive agent [105], a monoclonal antibody to the RANKL; which is a key regulator of bone resorption |
| Evidence of efficacy | In postmenopausal women, subcutaneous denosumab 6-monthly improved the BMD in both the spine (9%) and the hip (6%) [106]. It reduced the fracture risk: hip (40%), and nonvertebral (20%). In contrast to bisphosphonates, long-term denosumab results in continued improvement in BMD [107]. Further, switching to denosumab in those who had long-term bisphosphonates induced greater BMD gains over 12 months of treatment [108]. Therefore, this approach may be preferable when a response to intravenous bisphosphonates is inadequate. |
|
| Important side effects/drawbacks | The effect of denosumab is reversible, thus a loss in BMD may happen after treatment cessation [109]. Therefore, it is advocated to continue with an antiresorptive agent after stopping denosumab [110]. | |
| 2. Anabolic agents | ||
| 2a. Parathyroid hormone 2nd or 3rd line in management |
Mechanism of action | The recombinant parathyroid hormone fragment (1–34 or teriparatide) results in increased bone formation when administered intermittently [111]. |
| Evidence of efficacy | Used to treat corticosteroid-related bone loss and also in postmenopausal osteoporosis with beneficial effects on BMD and reduction in vertebral and nonvertebral fractures. | |
| Important side effects/drawbacks | Many guidelines restrict its use to two years in those patients at high risk of/or documented vertebral fractures [96] because of an increased risk of osteosarcoma found in studies in rodents, but this has not been seen in human studies. Therefore, the new teriparatide label [112] states that use for more than 2 years may be allowed in patients having a high risk for fracture. It needs to be avoided when there is a heightened risk for osteosarcoma. Its effect is reversible, thus if discontinued a decline in BMD may follow. | |
| 2b. Romosozumab2nd or 3rd line in management. The main indication is postmenopausal osteoporosis. |
Mechanism of action | A humanized monoclonal antibody to sclerostin (a glycoprotein blocks canonical Wnt signaling bone formation pathway). It improves bone strength by increasing bone formation and suppressing bone resorption |
| Evidence of efficacy | Monthly subcutaneous administration (maximal 12 months) decreases the occurrence of vertebral fractures in postmenopausal osteoporosis [113]. | |
| Important side effects/drawbacks | There is concern about a possible increase in cardiovascular events [114]. It is mainly indicated for severe postmenopausal osteoporosis. | |
Abbreviations: BMD = bone mineral density; ONJ = osteonecrosis of the jaw; RANKL = receptor activator of nuclear factor kappa-B ligand; CTX = serum C-telopeptide of type I collagen; P1NP = procollagen 1 N–terminal propeptide.