Criteria for initiation of pharmacological treatment
The goals of osteoporosis treatment are prevention of fracture as a complication and maintenance of good skeletal health. Important strategies to reduce the fracture risk in osteoporotic patients are treatment with a bone resorption inhibitor or bone formation stimulant and guidance to establish a lifestyle that leads to maintenance and enhancement of bone strength and to avoid risk factors for fractures, such as a fall, that are independent of a decrease in bone strength.
The risk factors for fracture include low BMD, factors that contribute to a decrease in BMD, and deterioration of bone matrix, including lifestyle-related diseases. A prevalent fragility fracture is the most important among all these factors with the exception of low BMD. Family history of proximal femoral fractures significantly increases the fracture risk even in persons without a fragility fracture who have a “low bone mass” based on their BMD.
Based on this new knowledge about risk factors and the consideration about using FRAX® (see “Risk factors for fracture”), the criteria for initiating pharmacological treatment to prevent fragility fracture was established as shown in Fig. 8. In these criteria, FRAX® is used to consider whether or not to initiate pharmacological treatment in persons without a fragility fracture who have a low bone mass. This is because persons with a fracture risk comparable to patients with osteoporosis possibly could be included in this group and need other measures to assess the magnitude of the fracture risk other than low BMD. Considering that the 10-year probability of major osteoporotic fractures in the patients receiving pharmacological treatment was observed around 15 % in Japanese clinical settings, we adopted 15 % as a treatment threshold for the persons with low bone mass. In the guidelines, FRAX® is not used in the first-line screening to determine the persons who need further examination such as bone densitometry. As stated earlier, the cutoff value for the screening in Japan is being studied. The cutoff value of a 15 % 10-year probability is used for women and men younger than 75 years old, because almost all of the persons of this age group have a value above 15 % and thus its power as a cutoff value is too weak.
Evaluation of response to treatment
The optimal method for bone mass measurement to evaluate the therapeutic effect is DXA at the lumbar vertebrae on the anteroposterior direction, because it is sensitive enough to detect changes in bone mass. If the bone mass cannot be measured precisely at the lumbar vertebrae, measurement at the total hip is recommended. The timing of measurement should be determined based on the least significant change of each method.
The efficacy of drugs with significant effects on bone metabolism can be evaluated by measuring bone metabolic markers. It is beneficial to measure bone resorption markers at 3 to 6 months after the initiation of treatment and bone formation markers every 6 to 12 months. Attention should be paid to the minimum significant change of each marker.
Plain radiography is useful for detection of incident vertebral fractures after the initiation of treatment. CT, MRI, and bone scintigraphy are sometimes required for confirmation of minor fractures, incomplete fractures, and unapparent fractures, and for differentiation from other clinical conditions including tumors.
QOL assessment using the Japanese Osteoporosis Quality of Life Questionnaire (JOQOL) is useful also for evaluation of therapeutic effects.
Basic treatments (non-pharmacological treatment)
A daily intake of calcium (700 to 800 mg) is recommended to optimize the effect of pharmacological treatment. It has been reported that calcium derivatives and calcium supplements may increase the risk of cardiovascular diseases. However, dietary intake of the same amount of calcium has not been shown to increase cardiovascular risk. Moreover, those adverse findings were reported from outside Japan, where calcium intake, serum lipid levels, and BMI are different from those in Japan. At this time, calcium as a medicine or supplement should not exceed 500 mg per dose.
Vitamin D (recommended daily intake, 10 to 20 μg) and vitamin K (250 to 300 μg) are also essential, and they should be prescribed to be taken as a medicine when it is difficult for the patient to obtain a sufficient amount from dietary sources. Hyperhomocysteinemia due to vitamin deficiency (vitamins B6, B12, and folic acid) involved in homocysteine metabolism has been shown to be a BMD-independent risk factor for fracture. It is recommended to warn patients not to consume excessive amounts of phosphorus, salt content, caffeine, and alcohol.
It has been demonstrated that high-impact activities, resistance exercises, back muscle exercises, stretching exercises, aerobic exercises, walking, and balance training can increase BMD and prevent vertebral fractures and falls in patients with osteoporosis.
In terms of pain relief, few data from randomized controlled trials are available about the effects of various physical therapies, nerve blocks, and surgeries; however, the efficacy of some drugs has been demonstrated.
These Guidelines detail the effect of each therapeutic agent used in Japan on BMD and the risk of vertebral fracture, non-vertebral fracture, and proximal femoral fracture, based on evidence from Japan and abroad. Each recommendation is also graded (Table 1). In regard to some therapeutic agents, the effect on QOL is also described. Table 2 shows the prescription drugs covered by the public health insurance in Japan.
For the selection of therapeutic agents, the full range of drug-related information must be considered: the efficacy of each medicine on BMD, fracture risk, QOL including pain, bone metabolic markers, risk of fall, as well as safety, including effects other than those on bone metabolism per se and adverse effects. Further, the patient’s clinical state must be considered.
The systematic review published by MacLean and colleagues indicated that bisphosphonates (alendronate and risedronate) are a first-line agent for patients at high risk of vertebral, non-vertebral, or proximal femoral fracture . Parathyroid hormone derivatives are first-line agents for patients at high risk of vertebral or non-vertebral fracture. Selective estrogen receptor modulators (SERMs) are first-line agents for patients at high risk of vertebral fracture. Minodronic acid, a bisphosphonate developed in Japan, is expected to be used for the high-risk group for vertebral fracture. Eldecalcitol, an active vitamin D3 derivative developed in Japan, is expected to be used for the high-risk group for vertebral or non-vertebral fracture. However, more data are required for these new agents.
A postmenopausal decrease in bone mass is caused by estrogen deficiency. Therefore, estrogen replacement has been considered to be an effective treatment option for osteoporosis since early times. Estrogen replacement is useful also for prevention and treatment of other diseases and symptoms caused by estrogen deficiency. Administration of estrogen to young amenorrheic women or relatively young postmenopausal women can prevent osteoporosis. Estrogen is also useful for treatment of osteoporosis in women with climacteric symptoms in relatively early stage of postmenopause. Conjugated estrogen, estradiol, and estriol are the approved estrogen derivatives in Japan.
Although conjugated estrogen increases BMD and prevents vertebral, non-vertebral, and proximal femoral fracture, it is not covered by the public health insurance in Japan for the treatment of osteoporosis.
Estradiol increases BMD, but there is little evidence that it prevents fractures.
There is almost no evidence about the effects of estriol.
Alfacalcidol and calcitriol (active vitamin D3 derivatives)
Alfacalcidol and calcitriol are active vitamin D3 derivatives. Alfacalcidol, developed in Japan, is a prodrug requiring hydroxylation in the liver for activation. Because these derivatives were approved for the treatment of osteoporosis in 1983 and 1989, respectively, there is insufficient large clinical trial data. However, several reports suggested these agents maintain lumbar BMD at a significantly higher level as compared to placebo, or reduce the risk of vertebral and non-vertebral fractures (not statistically significant; Fig. 9a) .
It has been reported also that vitamin D deficiency causes atrophy of the type II muscle fibers, and that vitamin D supplementation improves trunk imbalance. Active vitamin D3 derivatives (alfacalcidol and calcitriol) reduce falls among the elderly (Fig. 9b) . These active vitamin D3 derivatives have been confirmed to be safe, even for long-term use, and they are recommended for the elderly (see “Combination therapy” for combination with bisphosphonate).
Eldecalcitol (active vitamin D3 derivative)
Although the conventional active vitamin D3 derivatives have been reported to be effective for preventing fractures, they have not been shown to increase BMD significantly. Various vitamin D3 derivatives have been investigated; of these eldecalcitol was developed in Japan. Eldecalcitol showed superior efficacy to alfacalcidol to increase BMD (Fig. 10a) , while its effect on calcium absorption was nearly unchanged. Eldecalcitol may exert its actions by promoting calcium absorption from the small intestine, similar to the conventional active vitamin D3 derivatives, and prevent bone resorption by inhibiting osteoclastic function.
In a comparative study of eldecalcitol and alfacalcidol, the incidence of vertebral fractures was found to be significantly lower in the eldecalcitol group (Fig. 10b) . While there was no significant difference in the overall incidence of non-vertebral fractures between the eldecalcitol and alfacalcidol groups, there was a trend towards a greater decrease in the incidence of non-vertebral fractures at the three major sites (humerus, wrist, and hip) in the eldecalcitol group than in the alfacalcidol group (Fig. 10c) . Of note, the incidence of wrist fractures was significantly reduced in the eldecalcitol group.
Clinical trials of eldecalcitol have been conducted in patients over a wide range of age and severity, and this agent can be used across the entire spectrum of patients with osteoporosis.
Menatetrenone (vitamin K2 derivative)
In elderly women and patients with osteoporosis being treated with a bisphosphonate, insufficient intake of vitamin K is a BMD-independent risk factor for fractures. Menatetrenone, a vitamin K2 derivative, promotes carboxylation of osteocalcin, and thereby it reduces the serum level of ucOC, an index of vitamin K deficiency.
Menatetrenone slightly increases lumbar BMD and reduces vertebral and non-vertebral fractures (Fig. 11) . Menatetrenone is considered to exert its fracture-reducing effect via a mechanism of action other than increasing BMD.
Notably, for etidronate, a first-generation bisphosphonate, there is a small margin between its serum level for the onset of its inhibitory actions on bone resorption and the serum level for its inhibitory effects on bone formation. Close attention must be paid to its narrow safety range. Thus, a cyclical intermittent treatment strategy (200 to 400 mg/day once daily for 2 weeks, followed by a rest period of 10 to 12 weeks) is essential.
Because etidronate reduces bone resorption, it is effective particularly for high-turnover osteoporosis, and it maintains bone mass even in low-turnover osteoporosis. Etidronate reduces blood and urine levels of bone metabolic markers. Etidronate reduces incident vertebral fractures in patients who have vertebral fractures. There is no clear evidence about whether or not etidronate reduces non-vertebral fractures.
Alendronate, a second-generation bisphosphonate, has a very wide safety range. Its inhibitory effect on bone resorption is exerted at a much smaller dose than the dose for its inhibitory effect on bone formation (approximately 1/6,000).
Many clinical trials and meta-analyses have shown that alendronate increases BMD, reduces fractures at the vertebra/non-vertebra, proximal femur, and distal end of the forearm; and improves the bone metabolic marker profile. Alendronate has been reported to reduce vertebral fracture and increase lumbar BMD also in men with osteoporosis.
In terms of QOL, a decrease in the duration of bed rest for low back pain, a decrease in the days of activity restriction, and improvement of arthralgia and pain-related QOL scores after treatment with alendronate have been reported (see “Combination therapy” for the combination with active vitamin D3 derivatives).
A once-weekly dose of alendronate (35 mg), compared to a daily dose of alendronate (5 mg) was shown to have a similar effect on lumbar BMD and urinary levels of type I collagen cross-linked N-telopeptides (NTX); the incidence of adverse reactions and drug discontinuation was lower in the once-weekly group.
Risedronate, a third-generation bisphosphonate, has a strong inhibitory effect on bone resorption.
Many clinical trials and meta-analyses have shown that risedronate increases BMD and reduces fractures at the vertebra/non-vertebra and proximal femur in postmenopausal women. Risedronate was reported to increase lumbar BMD also in men with osteoporosis. Large-scale clinical trials in North America, Europe, and Australia have shown preventive effects with risedronate against incident vertebral fracture from the first year of treatment. In Japan, it was reported that risedronate improved scores for body pain, vitality, and social functioning in QOL assessment using the SF-36 scale.
Once-weekly risedronate (35 mg), compared to daily risedronate (5 mg), was shown to increase BMD at the femoral neck and trochanter to the same degree in a study in the USA. In a Japanese clinical trial, once-weekly risedronate (17.5 mg), compared to daily risedronate (2.5 mg), increased lumbar BMD to the same degree at 48 weeks.
Minodronic acid (bisphosphonate)
Minodronic acid is the only domestically developed bisphosphonate for osteoporosis, and the only bisphosphonate which has been investigated for its inhibitory effect on fracture in Japanese patients at doses approved in Japan. Minodronic acid has the strongest inhibitory effect on bone resorption among the bisphosphonates currently available in Japan.
The efficacy of minodronic acid on BMD at the lumbar spine and total hip is equivalent to alendronate (Fig. 12a) . In addition, minodronic acid significantly increased BMD in patients who had a poor response to other bisphosphonates.
Minodronic acid reduced vertebral fracture risk by 59 % in Japanese patients with osteoporosis (Fig. 12b) , and no difference was observed in the effect between patients above and below 75 years of age. No clinical trial to determine the effect of minodronic acid on non-vertebral fracture or proximal femoral fracture has been conducted. The results of the ongoing Japanese Osteoporosis Intervention Trial (JOINT)-04 initiated in 2011 by the Adequate Treatment of Osteoporosis (A-TOP) Research Group (see “Combination therapy”) are greatly anticipated to answer these questions. Minodronic acid is available for daily use (1 mg) and once every 4 weeks (50 mg).
Raloxifene, a selective estrogen receptor modulator, binds to the estrogen receptor (ER) with an affinity equivalent to estrogen and induces a conformational change at the helix 12 in the C-terminal part of ER; this conformational change produced by raloxifene is different from that produced by estrogen. Thus, raloxifene has a tissue-selective pharmacological action: it shows estrogen-like effects on bone, but not on the breast or uterus.
The Multiple Outcomes of Raloxifene Evaluation, a large-scale randomized controlled trial with 7,705 patients in 25 countries, demonstrated that raloxifene increased BMD and reduced incident vertebral fractures, regardless of the presence or absence of prevalent vertebral fractures and even in subjects with low bone mass (osteopenia). Additionally, raloxifene significantly reduced the incidence of non-vertebral fractures in patients with severe vertebral fractures. In Japan, a 3-year post-marketing surveillance demonstrated that the overall incidence of clinical fractures was as low as 1.2 %.
Many observational studies from Japan and abroad demonstrated the effect of raloxifene on QOL, including pain relief. A meta-analysis revealed that raloxifene decreases the overall mortality by 10 %.
Venous thromboembolism is one of the clinically important adverse events of SERMs. The incidence of venous thromboembolism in patients treated with raloxifene is 0.2 %, stated in the drug package insert, based on the results of a 3-year post-marketing surveillance conducted in 7,557 Japanese patients.
Bazedoxifene, a SERM, has an estrogen-like action selectively on bone metabolism and lipid metabolism, but not on the breast or uterus.
An international multi-center clinical trial demonstrated that bazedoxifene increases BMD and reduces vertebral fractures, similar to raloxifene. Although no overall reduction on non-vertebral fractures was observed with bazedoxifene, the incidence of non-vertebral fracture in postmenopausal women at a higher risk of fracture was significantly reduced by bazedoxifene as compared to placebo and raloxifene. Additionally, the higher the FRAX® score, the more effectively bazedoxifene reduced osteoporotic fractures. Bazedoxifene was also reported to improve the profile of bone metabolic markers. The effect of bazedoxifene on proximal femoral fracture has not been studied yet.
A significant decrease in the incidence of vertebral fractures and the safety of the drug were consistently observed during the 5-year treatment with bazedoxifene.
Calcitonin is a bone resorption inhibitor acting directly on osteoclasts and pre-osteoclasts to control their functions. Calcitonin also relieves pain via the central serotoninergic system, and therefore its derivatives may be the first choice to obtain pain relief and improves QOL in the early phase after the occurrence of osteoporotic fractures or in patients with postural distortion associated with vertebral fractures.
There are some reports on the effect of calcitonin derivatives on BMD and vertebral fracture (Fig. 13a) , but none on non-vertebral or proximal femoral fractures.
Some randomized clinical trials and systematic reviews revealed significant reductions in the severity of pain associated with ADLs 1 to 4 weeks after calcitonin was started (Fig. 13b) . In terms of QOL, improvement in SF-36 scores, pain relief, and improved ADLs, and an enhanced effect of rehabilitation in patients who had a total hip replacement after proximal femoral fracture was reported.
Outside of Japan, intra-nasal formulations of calcitonin derivatives are used primarily, and a preventive effect on fractures and beneficial effect on pain was observed. However, the increased risk of cancer was reported from the European Medical Association (EMA) in patients treated with calcitonin and intra-nasal calcitonin was withdrawn from the European market.
Although antibodies might be produced after injection of calcitonin derivatives, they do not influence the effect of calcitonin and are not involved in the side effects of calcitonin derivatives. Therefore, patient monitoring is not needed.
Teriparatide (recombinant human parathyroid hormone)
Unlike bone-resorption inhibitors, intermittent administration of teriparatide (a recombinant form) as a daily subcutaneous injection specifically increases serum P1NP, a bone formation marker, indicating promotion of bone remodeling followed by the formation of bone tissue.
Teriparatide, given as a daily subcutaneous injection, is recommended in patients at high risk of fractures such as patients who have had a fracture(s) while being treated with a bisphosphonate or SERM, elderly patients with multiple vertebral fractures or proximal femoral fractures, or patients with significantly reduced BMD. The combination of teriparatide with an oral bisphosphonate is not recommended.
Teriparatide increases BMD at the lumbar vertebrae and proximal femur, and reduces vertebral and non-vertebral fracture. The incidence of a radial fracture is reduced with teriparatide, while the apparent BMD of the radius is slightly decreased in association with the formation of new bone matrix, and the external diameter of the radius is increased. A meta-analysis revealed that teriparatide reduces low back pain.
Teriparatide (a recombinant form) approved in Japan is self-injected daily at home, after instruction by physicians or nurses. The total dosing period is limited to 24 months. After 24 months of treatment with teriparatide, adequate treatment with a bone-resorption inhibitor is recommended to maintain the bone strength.
Osteoporosis is a multifactorial disease, thus combination therapy with agents with different mechanisms of action is considered reasonable. However, the efficacy of combination therapy lacks evidence at this time.
The Adequate Treatment of Osteoporosis (A-TOP) Research Group was authorized in the year 2000 by the Japan Society of Osteoporosis and assisted by the Public Health Research Foundation to obtain clinical evidence regarding osteoporosis treatment. It conducted a clinical trial comparing monotherapy with alendronate, a new bisphosphonate at the time, and combination therapy with alendronate and alfacalcidol, an active vitamin D3 derivative developed in Japan (Japanese Osteoporosis Intervention Trial: JOINT-02). The incidence of vertebral fracture was significantly reduced in the combination therapy group during the first 6 months of treatment, and in both subgroups of patients with multiple vertebral fractures and grade 3 vertebral fractures by semiquantitative assessment during the 2-year treatment period (Fig. 14) . The incidence of non-vertebral fracture (weight-bearing bones) was also significantly reduced in the combination therapy group. Based on these results, combination therapy with alendronate and an active vitamin D3 derivative is recommended for the prevention of incident vertebral and non-vertebral fracture in patients at a high risk of fracture.