Osteoporosis is a systemic disorder of bone metabolism characterized by decreased bone mass, degradation of bone microstructure, and increased bone fragility resulting in increased risk of fracture. Osteoporotic fractures are the most serious consequence of osteoporosis. Anti-osteoporotic drug therapy can reduce the incidence of osteoporosis-related fractures, but its long-term therapeutic effects are controversial.
Currently, the commonly used anti-osteoporosis drugs include the following. (1) Vitamin D and calcium, which are the first-line drugs for the prevention of osteoporosis. (2) Anti-bone resorption drugs: such as bisphosphonates, estrogens, selective estrogen receptor agonists (represented by raloxifene) and calcitonin, etc. These drugs can inhibit osteoclastic bone resorption and slow down the process of bone loss. (3) Pro-bone formation drugs: such as parathyroid hormone, teriparatide, fluoride, these drugs can promote the osteoblast bone formation effect. (4) Other drugs: such as statins, denosumab, etc.
1.Is the anti-fracture effect of anti-osteoporosis drugs long-lasting?
The anti-osteoporotic fracture effect of many drugs is most pronounced within the first year of treatment when compared with placebo controls.
In order to observe the efficacy of prolonged drug treatment, many trials have been conducted with extensions. Two examples are briefly listed here.
(1) The Evista trial provided data after 8 years of raloxifene treatment. at the end of the 8-year follow-up, it was found that raloxifene did not have a significant preventive effect on the occurrence of nonvertebral fractures.
(2) The longest study of risedronate was a 7-year follow-up of 68 study subjects. It was found that the incidence of vertebral fractures was essentially the same in patient years 0-3 years of drug use versus 6-7 years.
From the studies available to date, there is no clear evidence that anti-osteoporosis treatment for more than 3-5 years has a better anti-fracture effect.
2. Is there a risk of stopping anti-osteoporosis drug therapy?
The prognosis after stopping treatment varies significantly from drug to drug. A few examples are briefly listed.
(1) Discontinuation of anti-osteoporosis therapy leads to a decrease in bone mineral density, which is more pronounced in patients on estrogen replacement therapy.
In 81 patients studied, after taking combined estrogen (0.625 mg/d) for two consecutive years and then switching to placebo for one year, follow-up revealed a 4.5% and 2.4% decrease in bone mineral density in the spine and femoral rotor ridge, respectively.
and 2.4%, respectively. Estrogen replacement therapy reduced the occurrence of hip and spine, with a 2.4% decrease in lumbar spine BMD one year after stopping raloxifene.
(2) Bone mass also decreases after stopping denosumab treatment, with one study finding the most significant decrease in BMD one year after stopping treatment.
(3) In the HORIZON clinical study for zoledronic acid, patients were treated with zoledronate for 3 years and then some patients were switched to placebo treatment for 3 years of follow-up. At the end of the study, a mild decrease in BMD was found in the group switching to placebo treatment compared to the group taking zoledronate for 6 years, but there was no significant difference in bone resorption markers.
3. Is it harmful to extend the duration of treatment with anti-osteoporosis drugs?
Anti-osteoporosis drugs have many adverse effects, such as gastrointestinal upset with oral bisphosphonates, nephrotoxicity with intravenous bisphosphonates, increased risk of venous thrombosis with raloxifene, etc. However, there is no evidence that the incidence of such adverse reactions increases with the duration of drug use.
(1) One of the more serious complications of intravenous bisphosphonate use in people with severe bone disease is osteonecrosis of the jaw. The incidence has been reported in the United States to be between 1/10,000 and 1/100,000. However, to date, there is insufficient evidence that bisphosphonates increase the incidence of osteonecrosis of the jaw. The 2191 patients who were followed up for less than 2.5 years with continuous use of these drugs did not have this complication.
(2) Two cases of osteonecrosis of the jaw were identified in 2343 patients treated with denosumab for 6 years. Cases of mid-femoral fractures caused by denosumab have been confirmed, but the occurrence of fractures may be related to the length of treatment.
It can be seen that the side effects of anti-osteoporosis drugs do exist, but they are very rare.
4.Insights for clinical workers
In the process of osteoporosis treatment, two misconceptions must be avoided.
(1) “There is no evidence that the anti-osteoporotic effect will last more than 5 years, so treatment should be stopped.”
Physicians who hold this view do not consider the patient’s high risk of fracture.
(2) “Like hyperlipidemia, osteoporosis is a chronic disease and medication cannot be stopped; anti-osteoporosis treatment is concomitant for life.”
Unlike other chronic disease treatments, anti-osteoporosis treatment leads to changes in bone weight or structure that will not be reversed.
Therefore, our treatment should follow the principle of individualization.
So what criteria should be used to determine the treatment plan?
The answer is that the long-term treatment plan for patients with osteoporosis depends on the patient’s specific situation and the protocol of the initial treatment. Specific clinical situations are addressed as follows.
(1) An elderly and frail female patient should be considered for a course of anti-osteoporosis drug therapy based on the presence of comorbid neurological disease or a history of previous fractures. Risk of fracture, history of previous fractures, bone mineral density, and age are all indicators for assessing the need for anti-osteoporosis medication in an individual and can also be used to determine the course of treatment.
(2) Patients are at a higher risk of re-fracture within a short period of time after their first fracture, so receiving medication within a short period of time after the initial fracture is a better choice. However, the risk of re-fracture decreases over time, so how do you decide the duration of anti-osteoporosis medication for your patients at this time?
Bone mineral density is a good predictor of a patient’s risk of re-fracture. It has also been shown that persistent osteoporosis of the femoral neck predicts the need for long-term anti-osteoporosis therapy.
(3) Since BMD can help physicians determine whether a patient needs a longer course of treatment, is BMD itself an indicator of the efficacy of anti-osteoporosis treatment?
The answer is not certain. Because the relationship between the anti-osteoporotic effect of drugs such as alendronate, risedronate, and raloxifene and the change in BMD due to the drug itself has not been proven, but zoledronate as well as denosumab have been validated. Compared to bisphosphonates, denosumab can increase BMD to a large extent, with a higher likelihood of BMD attainment.
For severe patients with very low BMD, a combination regimen can be used to correct BMD values (e.g. teriparatide or osteosclerosis protein inhibitors for initial treatment plus other classes of drugs to prolong the therapeutic effect).
(4) Because of the significant differences in response to discontinuation of different anti-osteoporosis drugs, it is not necessary for all patients to stop treatment on schedule.
Treatment can be extended on a patient-by-patient basis for patients treated with bisphosphonates, but not for patients on estrogen replacement therapy. Patients with fracture sparing who discontinue drug therapy must be monitored regularly for bone resorption markers as well as bone mineral density.
(5) The decision to extend therapy must be based on an assessment of fracture risk.
Treatment with bisphosphonates for 3-5 years can be discontinued. However, in patients with a high fracture risk, discontinuation of therapy is not a wise choice, but the possibility of drug side effects must be considered.