Postmenopausal Osteoporosis Postmenopausal Osteoporosis (PMO) ((PMO) ( 停經後骨質疏鬆症停經後骨質疏鬆症 ))

郝 立 智 醫 師郝 立 智 醫 師Clifford J. Rosen, M.D. Clifford J. Rosen, M.D.

NEJM, Volume 353:595-603 August 11, 2005 Number 6

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OutlineOutlineCase PresentationThe Clinical Problem Strategies and Evidence Overview Planning an Intervention Strategy Nonpharmacologic Options

         Physical Activity Pharmacologic Options

         Antiresorptive Agents          Postmenopausal Hormone-Replacement Therapy          Selective Estrogen-Receptor Modulators          Bisphosphonates          Calcitonin          Strontium Ranelate          Anabolic Agents          Combination Therapy

Areas of Uncertainty Guidelines Summary and Recommendations

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Case PresentationCase Presentation A 63-year-old woman presents with a history of acute low back pain. She had menopause at 44 years of age but never received postmenopausal hormone-replacement therapy. She reports a history of a Colles' fracture at the age of 60 years. Her mother sustained a hip fracture at 70 years of age.Lumbar-spine films reveal a new vertebral fracture. Dual-energy x-ray absorptiometry (DEXA) of the hip shows a BMD T score of –1.3. How should her case be managed?

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The Clinical Problem (1)The Clinical Problem (1) PMO is a common disease with a spectrum ranging from asymptomatic bone loss to disabling hip fracture. The National Institutes of Health consensus conference defined osteoporosis as a disease of increased skeletal fragility accompanied by low BMD (a T score for BMD below –2.5) and microarchitectural deterioration. In the United States, there are 1.5 million osteoporotic fractures per year, with an annual direct cost of nearly $18 billion. It is predicted that the prevalence of fracture will increase by the year 2025, yet less than a quarter of all women who sustain an osteoporotic fracture currently receive appropriate Tx for osteoporosis.

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The Clinical Problem (2)The Clinical Problem (2)Fractures occur because of qualitative and quantitative deterioration in the trabecular and cortical skeleton. Bone quality cannot be measured clinically, but BMD can be measured painlessly, quickly, safely, accurately, precisely, and relatively inexpensively; several methods are available, DEXA is currently the most validated. Low bone mass at any skeletal site is associated with a substantially increased risk of fracture. Other risk factors include advancing age, low BW, maternal history of osteoporosis, the direction of a fall (a fall backward and to one side is most likely to result in a fracture), and most important, the presence of a previous fracture. These and other risk factors for osteoporosis were reviewed in a recent Clinical Practice article in the Journal (Screening for osteoporosis. N Engl J Med 2005;353:164-171.).

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世界衛生組織 (WHO) 對於骨質疏鬆症的分級方式：

Definition Category QUI/Stiffness T-score

Within 1SD of the young adult reference mean

Normal T > -1.0

More than 1SD below young adult mean, but less than 2.5 SD below this value

Low Bone Mass(Osteopenia)

-1.0 > T > -2.5

2.5 SD or more below the young adult

Osteoporosis T < -2.5

More than 2.5 SD below young adult mean in the presence of one or more fragility fractures

Severe Osteoporosis(established osteoporosis)

T < -2.5

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國內對於骨質疏鬆症的分級方式： QUI/Stiffness T-

scoreCategory

T > -1.0 Normal

-1.0 > T > -2.0 Grade 1 Osteoporosis

-2.0 > T > -3.0 Grade 2 Osteoporosis

-3.0 > T > -4.0 Grade 3 Osteoporosis

-4.0 > T Grade 4 Osteoporosis

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Normal bone trabeculae Bone trabeculae with osteoporosis

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Figure 1. DEXA of the Spine and Hip of a 66-Year-Old Postmenopausal Figure 1. DEXA of the Spine and Hip of a 66-Year-Old Postmenopausal

Woman.Woman. Dx of osteoporosis can be made on the basis of BMD of the hip (Panel A) and the spine (Panel B). The density of lumbar vertebrae 1 through 4 (L1 through L4), both as a percentage of the mean value for a young adult and as a T score, does not indicate osteoporosis, because of the high values for L3 and L4. Since the latter probably reflect OA changes in the spine, the use of the two lowest values is recommended for diagnosis.Note that in this p't the T scores at the hip are relatively high, as compared with the spine. The density of the total hip includes the lesser trochanter and adjacent cortical bone and thus has a higher value. The red lines on the left side of each panel indicate the specific area being measured, and the blue areas on the right side indicate the expected age-related means (±1 SD) for white women. BMD measurement results in less than 10 mrem of radiation exposure, as compared with 30 to 60 mrem for a CXR. The color stripes in each panel indicate the degree of concern related to bone density; red denotes high concern and green low concern.

Screening for osteoporosis. N Engl J Med 2005;353:164-171.

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Figure 2.Figure 2. Flow Chart for Recommendations Regarding Selection of p'ts for DEXA. Flow Chart for Recommendations Regarding Selection of p'ts for DEXA. For peripheral densitometry, each system will have different levels of T-score cutoff. In most cases, DEXA will be recommended for p'ts with T scores of –1.0 or lower. It is important to identify diseases or drugs that are likely to cause skeletal fragility or to increase the risk of falls. Risk factors that warrant BMD testing include an age of more than 65 years, a personal history of fracture (particularly fragility fracture) or height loss of more than 2 cm, a family history of fracture in a first-degree relative, low BW (less than 126 lb), and recent weight loss (more than 5 %). Other risk factors include female sex, late menarche, early menopause, low Ca intake, vit D insufficiency, smoking, excess alcohol intake, physical inactivity and muscle weakness, and impaired vision or balance. Secondary causes include hyperparathyroidism, hyperthyroidism, Cushing's syndrome, glucocorticoid therapy, inflammatory disorders (including arthritis, bowel disease, and pulmonary disease), hypogonadism (including Tx with LHRH agonists and aromatase inhibitors), cancer (especially hematologic conditions), congenital disorders (including osteogenesis imperfecta and homocystinuria), and neurologic disorders (including immobilization and Tx with antiepileptic drugs).

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Strategies and Evidence– OverviewStrategies and Evidence– Overview (1) (1)A comprehensive management plan includes evaluation of those at highest risk, exclusion of secondary causes of low BMD, and selection of the appropriate Tx. A history of fragility fractures (unrelated to substantial trauma) in a postmenopausal woman strongly supports a diagnosis of osteoporosis, regardless of BMD.Secondary causes such as primary hyperparathyroidism, Vit D deficiency due to low intake, lack of exposure to sunlight, or malabsorption, and multiple myeloma should be excluded, particularly if the z score (the number of standard deviations from the mean for an age- and sex-specific reference group) for BMD is depressed (i.e., below –2.00).Biochemical markers of bone turnover such as N-telopeptide or osteocalcin rarely help in establishing a diagnosis or selecting Tx, although they may be useful in determining whether there is accelerated bone loss, particularly during the first few years of menopause.

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OverviewOverview (2) (2)Decision making should also take into account several caveats. Osteoporosis therapy can reduce the risk of fracture by as much as 50 %, but some women have fractures despite Tx. Also, changes in lifestyle and the use of pharmacologic interventions are lifetime commitments, and therefore cost, compliance with a medication regimen, and safety must be considered in decisions on therapy.

Moreover, a substantial percentage of osteoporotic fractures occur in women who have T scores above –2.5. (A T score is the number of standard deviations the BMD measurement is above or below the young-normal mean bone density.) In some cases, there is a substantial discrepancy between the spine and hip T scores. Thus, decisions with regard to Tx should not be based solely on BMD.

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Self-assessment of Osteoporosis 1.Height loss of more than 2.5 cm

2.Occiput fails to touch the wall when standing next to the wall 3.A bend back

These are clues that you may already have osteoporosis. Please consult your doctor if you have these problems.

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Planning an Intervention StrategyPlanning an Intervention StrategyTherapy for PMO is considered to be primary prevention when it is prescribed for those at risk without a T score below –2.5 or a history of fragility fracture and is considered to be Tx for those with established disease, including previous osteoporotic fracture, markedly reduced BMD, or both. The choice of an appropriate regimen will depend on whether the therapy is designed principally to prevent bone loss in p'ts with osteopenia (a T score between –1 and –2.5) or to reduce the likelihood of a first or subsequent fracture in osteoporosis.

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Nonpharmacologic Options (1)Nonpharmacologic Options (1) Ca supplementation should be adjunctive Tx for all women with established osteoporosis and must be part of any preventive strategy to ameliorate bone loss.Increased Ca intake reduces the hyperparathyroidism associated with advancing age and can enhance mineralization of newly formed bone. A recent meta-analysis of 15 Ca intervention trials involving healthy women and PMO demonstrated an increase of nearly 2 % in spine BMD after two years, although the risk of vertebral and nonvertebral fracture was not reduced to a statistically significant level. A total Ca intake of 1200 to 1500 mg/d (through diet, supplements, or both) is recommended for all postmenopausal women.

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Nonpharmacologic Options (2)Nonpharmacologic Options (2)Vit D is essential for skeletal maintenance and enhancement of Ca absorption. Dietary insufficiency of this Vit is a growing problem, with as many as two thirds of p'ts with hip fracture classified as having a deficiency of Vit D (defined as a serum 25-hydroxyVit D [25(OH) Vit D] level below 15 ng/ml [37.4 nmol/l]). Elderly persons with chronic conditions that require assisted-living situations are particularly vulnerable to Vit D deficiency because of lack of adequate exposure to sunlight.One large trial showed a reduction of 33 % in hip fracture among nursing home residents who were randomly assigned to receive Ca and Vit D, as compared with those given placebo.

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Vit D3 and CaVit D3 and Ca to prevent hip fractures in the elderly women to prevent hip fractures in the elderly women

BACKGROUND. Hypovitosis D and a low Ca intake contribute to increased parathyroid function in elderly persons. Ca and vit D supplements reduce this 2nd hyperparathyroidism, but whether such supplements reduce the risk of hip fractures among elderly people is not known. METHODS. We studied the effects of supplementation with vit D3 (cholecalciferol) and Ca on the frequency of hip fractures and other nonvertebral fractures, identified radiologically, in 3270 healthy ambulatory women (mean [+/- SD] age, 84 +/- 6 years). Each day for 18 months, 1634 women received triCa phosphate (containing 1.2 g of elemental Ca) and 20 micrograms (800 IU) of vit D3, and 1636 women received a double placebo. We measured serial serum PTH and 25-hydroxyvit D (25(OH)D) in 142 women and determined the femoral BMD at base line and after 18 months in 56 women.

N Engl J Med 1992;327:1637-1642.

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RESULTS. Among the women who completed the 18-month study, the number of hip fractures was 43 % lower (P = 0.043) and the total number of nonvertebral fractures was 32 % lower (P = 0.015) among the women treated with vit D3 and Ca than among those who received placebo. The results of analyses according to active Tx and according to intention to treat were similar. In the vit D3-Ca group, the mean serum PTH had decreased by 44 % from the base-line value at 18 months (P < 0.001) and the serum 25(OH)D had increased by 162 % over the base-line value (P < 0.001). The BMD of the proximal femur increased 2.7 % in the vit D3-Ca group and decreased 4.6 % in the placebo group (P < 0.001). CONCLUSIONS. Vit D3 and Ca reduces the risk of hip fractures and other nonvertebral fractures among elderly women.

N Engl J Med 1992;327:1637-1642.

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Nonpharmacologic Options (3)Nonpharmacologic Options (3)In another trial, Tx with a single oral dose of 100,000 IU of Vit D3 every four months reduced nonvertebral fractures by nearly a third among elderly people who are able to walk.Similarly, among older men and women in New England, Ca citrate (500 mg/d) and Vit D3 (700 IU/d) reduced the risk of nonvertebral fracture.There is strong evidence that Vit D enhances muscle strength and reduces the risk of falling.Table 1 lists the various forms of Ca and Vit D supplements.Counseling with regard to avoidance of smoking and excessive alcohol intake is routinely warranted, particularly since smoking and alcohol intake have been linked in some studies to greater fracture risk.

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Physical ActivityPhysical Activity Bed rest or immobility due to other causes can result in rapid bone loss. Moreover, the number of falls and the percentage of falls that result in fracture increase with age. A recent Cochrane meta-analysis found that muscle strengthening, balance training, assessment of the home for hazards, withdrawal of psychotropic medications, and the use of a multidisciplinary program to assess risk factors all protect against falls. Another approach is to pad the hip with a hip protector to reduce trauma during a fall; although p't compliance with this strategy is generally poor, when used properly, the strategy has been reported to reduce the risk of hip fracture. Regular physical activity, including aerobic, weight-bearing, and resistance exercise, is effective in increasing BMD of the spine and strengthening muscle mass in postmenopausal women, but there are no large trials establishing whether these interventions reduce the fracture risk.

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Pharmacologic OptionsPharmacologic Options An aggressive intervention program can reduce the risk of fracture and improve the quality of life among PMO. Several pharmacologic options are available, and these can be classified according to their mechanism of action. Two main classes of drugs:

1. Antiresorptive agents (agents that block bone resorption by inhibiting the activity of osteoclasts).

2. Anabolic agents (agents that stimulate bone formation by acting primarily on osteoblasts). Table 2 is a review of agents that have been approved by FDA.

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Antiresorptive Agents Antiresorptive Agents

By suppressing osteoclast activity, antiresorptive agents slow the remodeling cycle, thereby enhancing mineralization of the bone matrix and potentially stabilizing the trabecular microarchitecture. These agents increase BMD in women with osteopenia or osteoporosis and reduce the risk of fracture in women with osteoporosis, although efficacy varies among the agents (Table 2).

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  Postmenopausal Hormone-Replacement Postmenopausal Hormone-Replacement

Therapy(1)Therapy(1) HRT was once considered the primary therapy for PMO. Estrogen slows bone resorption by blocking cytokine signaling to the osteoclast, increases BMD, and reduces incidence of new vertebral fractures by nearly 50 %. Low-dose conjugated estrogens (0.3 or 0.45 mg/d) or ultra-low-dose estradiol (0.014 mg/d) also increases BMD, but the antifracture efficacy of these therapies has not been established.Among women in the Women's Health Initiative trial, in those randomly assigned to receive conjugated estrogens, with or without a progestin, the reduction in hip fracture was 33 %.

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Postmenopausal Hormone-Replacement Therapy(2)Postmenopausal Hormone-Replacement Therapy(2)

Discontinuation of estrogen results in measurable bone loss, although it is not certain whether discontinuation results in a greater fracture risk than continuation. Recent concern about the nonskeletal risks associated with long-term use of estrogen (including the risk of breast cancer and the risk of CV disease), coupled with the availability of other drugs to treat osteoporosis has markedly lessened enthusiasm for HRT in the Tx and prevention of osteoporosis.

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Risks and Benefits of Risks and Benefits of Estrogen Plus ProgestinEstrogen Plus Progestin in Healthy Postmenopausal Women in Healthy Postmenopausal Women

Principal Results From the Women's Health Initiative Randomized Controlled TrialPrincipal Results From the Women's Health Initiative Randomized Controlled Trial Context  Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain. Objective  To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States. Design  Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998.

JAMA. 2002;288:321-333.

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Interventions  Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). Main Outcomes Measures  The primary outcome was coronary heart disease (CHD) (nonfatal MI and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.

JAMA. 2002;288:321-333.

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Results  1. On May 31, 2002, after a mean of 5.2 years of follow-up, the data and

safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits.

2. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total CV disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index.

3. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

4. The absolute excess risk of events included in the global index was 19 per 10 000 person-years.

JAMA. 2002;288:321-333.

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Conclusions  1. Overall health risks exceeded benefits from use of

combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women.

2. All-cause mortality was not affected during the trial.3. The risk-benefit profile found in this trial is not

consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.

JAMA. 2002;288:321-333.

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Selective Estrogen-Receptor Modulators Selective Estrogen-Receptor Modulators

Raloxifene inhibits bone resorption through the same mechanism as do estrogens. Raloxifene increases spine BMD slightly and decreases the risk of vertebral fracture by 40 % in women with osteoporosis, but it has no effect on the risk of nonvertebral fracture. The risk of breast cancer is reduced with long-term use of raloxifene, although the drug is not approved for this indication. New selective estrogen-receptor modulators are currently in phase 2 and 3 clinical trials.

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Raloxifene (Evista)Raloxifene (Evista)婦女在停經或卵巢切除以後，由於雌激素的分泌逐漸減少，使其分布在血中的濃度逐漸下降，長時期後會影響骨骼蝕骨細胞的再吸收及骨骼生成的不平衡，導致骨骼流失速率急速增加，如此提高了骨質疏鬆症發生的機率，並且有可能會因此嚴重影響人生往後將近三分之一歲月的生活品質，甚至縮短了生命，由此可見補充雌激素的必要性。然而曾有報告指出，雌激素的補充會使得乳癌及子宮內膜癌的發生機率增加，這對於停經後出現較少更年期症候的婦女而言，補充雌激素與否，無疑是一項內心交戰。選擇性雌激素受器調節劑 (Selective Estrogen Receptor Modulators , SERMs)是一種合成物，經由結合在雌激素受體(estrogen receptor)，透過基因的調節，能夠在不同的組織中表現雌激素的特性或拮抗性。Tamoxifene是第一代有效的 SERMs，其在乳房組織表現抗雌激素的作用，但在骨骼、脂肪組織及子宮則表現雌激素作用，因此目前tamoxifene被核准的適應症為治療及預防乳癌。

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新一代的 Raloxifene 於 1997 年 12月經由美國 FDA核准，可使用在預防及治療停經後婦女骨質疏鬆症。目前在台灣健保給付的適應症為，治療停經後婦女因骨質疏鬆引起骨折者。Raloxifene在骨骼及脂肪組織表現雌激素作用，除了可降低骨骼蝕骨細胞的骨再吸收外，並且可降低骨骼轉換率 (bone turnover)，而使得骨質密度增加。 Raloxifene在乳房及子宮內膜則是表現抗雌激素作用，因此，停經後婦女服用raloxifene不會造成子宮內膜組織的增生，對於產生子宮內膜癌的危險性較低，並且對於罹患乳癌具高度危險群者， raloxifene亦是良好的選擇。Raloxifene亦如同雌激素般可降低總膽固醇及低密度脂蛋白(LDL)的血中濃度 ( 約 6-11%)，但並不會影響高密度脂蛋白(HDL)及三酸甘油脂 (triglycerides)的量，是否因此而具有心血管系統保護作用，仍須待臨床證實。

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Raloxifene的口服吸收率約為 60%，食物不會影響吸收，因此不拘飯前或飯後服用，一般建議的劑量為每日一次60mg。約 95%以上會與血漿蛋白結合，因此與其他高度蛋白結合藥物，如 clofibrate, indomethacin, naproxen, ibuprofen, diazepam, diazoxide等併用時需特別注意。在體內具有高度的肝首渡代謝效應，絕對生體可用率為 2%，肝功能不好的患者服用此藥需要監測肝功能指數。然而 raloxifene並非經由 cytochrom p450 途徑代謝，所以較少藥物交互作用問題，但與 ampicillin 或cholestyramine併用時， raloxifene的吸收率會降低；與warfarin併用時，會使得 prothrombin time縮短，因此需特別留意。Raloxifene經由肝首渡代謝後，會形成 glucuronide結合型態，主要經由糞便排泄，只有小於 1% 的未結合型態會由尿液排出。排除半衰期約 27.7 小時。

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Raloxifene在臨床上最常見的不良反應包括臉部潮紅 (25%)以及腿部抽筋 (leg cramps, 6%)，因此建議女性在停經初期 (early stage)的前兩年，為減低臉部潮紅的停經症候群，仍以使用荷爾蒙替代療法 (HRT)為佳，之後再使用 raloxifene。然而，使用荷爾蒙替代療法時的不良反應，如腹痛、陰道出血、乳房疼痛、胃脹氣等，在使用 raloxifene時則較少出現。但有研究指出，服用 raloxifene的婦女會導致靜脈血栓栓塞(thromboembolism)發生的危險性增加，尤其是在最初使用的前四個月，因此在長期不能活動 (如長期臥床休息、手術後 )期間，至少應在72 小時之前停止服藥，直到患者恢復行動能力。而進行長途旅行的患者，應注意要時常走動。此外，當有以下的情況時也不建議使用 : (1) 懷孕或準備懷孕的婦女。(2) 具有靜脈血栓栓塞 (thromboembolism)，包括深層靜脈血栓、肺栓塞以及網膜靜脈栓塞 (retinal vein thrombosis) 病史的婦女。(3) 對於 raloxifene 任何成分有過敏者。(4) 授乳婦女、停經前婦女及小孩。(5) 同時併用雌激素或荷爾蒙替代療法。由於 raloxifene的雙重特性：雌激素及抗雌激素作用，使其不僅可用在停經後婦女罹患骨質疏鬆症卻無法使用雌激素、荷爾蒙替代療法或biphosphonates ；亦可作為停經後婦女罹患骨質疏鬆症且有乳癌、子宮內膜增生傾向之另一種選擇。

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Bisphosphonates (1) Bisphosphonates (1) The most widely prescribed antiresorptive agents and are often considered first-line therapy for PMO. These agents suppress resorption by inhibiting the attachment of osteoclasts to bone matrix and enhancing programmed cell death. First-generation bisphosphonates include etidronate and clodronate; neither drug is approved for osteoporosis. Alendronate and risedronate, two second-generation nitrogen-containing bisphosphonates, have been shown in randomized trials to increase BMD in postmenopausal osteopenia or osteoporosis; in women with osteoporosis, they have been shown to reduce the incidence of hip, vertebral, and nonvertebral fracture by nearly 50 %, particularly during the first year.

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Bisphosphonates (2)Bisphosphonates (2)As is the case with other antiresorptive drugs, increases in BMD with alendronate or risedronate account for a small fraction of their antifracture efficacy.Hence, follow-up DEXA may substantially underestimate the reduction in fracture risk. Alendronate can be safely administered for at least seven years without adversely affecting bone strength. Moreover, discontinuation of long-term (five years or more) alendronate therapy results in minimal bone loss over the ensuing three to five years. Alendronate or risedronate once weekly has been shown to reduce the rate of drug-induced esophagitis, as compared with daily doses. In a recent one-year head-to-head study, alendronate increased spine and hip BMD slightly more than risedronate, although the clinical significance of this finding is uncertain.

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Alendronate (Fosamax) 於 FDA核准之適應症為：1. 用以治療及預防停經後婦女骨質疏鬆症 (1995 年 )2. 用以治療男性及女性因服用類固醇所引起的骨質疏鬆症(1996 年 )目前在台灣健保給付的適應症為：限停經後婦女因骨質疏鬆症引起骨折之病患，其肌酸酐廓清率(Clcr) 大於每分鐘 35 毫升者。Alendronate在臨床上最常見的不良反應主要在腸胃道方面，如食道炎、食道糜爛、食道潰瘍、吞嚥困難、消化不良、胃脹、腹痛。其他方面的副作用則有肌肉骨骼酸痛、便秘、脹氣、頭痛。若是與鈣質補充劑、制酸劑或其他口服製劑同時服用，可能會影響 alendronate的吸收。因此，投與方式為每日食用第一種食物、飲料或其他藥物前半小時伴以大量白開水服用。且為了減少對食道的刺激，在服藥後至少 30分鐘內需保持身體直立姿態，直到吃過第一種食物。並且錠劑不可咀嚼或吸吮。服用過量的 alendronate會導致低血鈣症、上腸胃道不適作用，如胃不舒服、心灼熱、食道炎、胃炎或潰瘍等情況，可給予牛奶或制酸劑，使其與 alendronate結合。但由於alendronate對食道有刺激性，所以對服藥過量的患者不可催吐，並且須使病人姿勢保持直立狀態。

HLJ

Alendronate口服的生體可用率在女性約為 0.78%，在男性約為 0.59%，食物會降低此藥的吸收。一般的建議劑量為每日一次 10mg。雖然不易自腸胃道吸收，但進入體內後，對於骨骼重建區域的親和力良好。在骨骼的半衰期可達十年。約有78%會與血漿蛋白結合。目前的資料顯示其不會被代謝，倘若沒被骨骼吸收，剩餘藥物以原型經由尿液及糞便排泄。年老者或患有輕度到中度腎功能不全者，不需調整劑量。但不建議使用於 Clcr 小於 35ml/min的患者。此外下列患者也不建議使用：1. 會延遲食道排空的食道不正常現象，如食道狹窄或弛緩不能。2. 無法站立或坐直至少 30分鐘者。3. 對於 alendronate 任何成分有過敏者。4. 低血鈣症者。5. 懷孕婦女、授乳婦女及小孩。

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Bisphosphonates (3)Bisphosphonates (3)IV pamidronate has been used to treat women who cannot tolerate oral bisphosphonates; however, its efficacy in reducing fracture has not been established. Acute and delayed hypersensitivity reactions can occur and its use is contraindicated in Vit D deficiency, since the drug can cause a precipitous drop in serum Ca levels. In 2005, ibandronate, at a dose of 2.5 mg/d or 150 mg monthly, was approved by FDA for both prevention and Tx of PMO. Daily ibandronate has been shown to reduce significantly the incidence of vertebral fracture in women with osteoporosis and to reduce incidence of nonvertebral fracture in women with severe osteoporosis (T score, below –3.0). IV zoledronate, which is approved for Tx of malignant hypercalcemia, multiple myeloma, and skeletal metastases, can suppress bone resorption and increase BMD in postmenopausal women for as long as one year after a single 4-mg dose. Phase 3 trials are under way to evaluate the safety and efficacy of this drug in reducing osteoporotic fracture.

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Calcitonin Calcitonin

Calcitonin is an endogenous peptide that partially inhibits osteoclast activity. Nasal calcitonin and subcutaneous calcitonin are approved for PMO. Although Tx of women with osteoporosis with nasal calcitonin at a dose of 200 IU/d has been shown to reduce the incidence of vertebral (but not nonvertebral) fracture in a single randomized trial, methodologic flaws in the study have limited enthusiasm for this agent. In placebo-controlled studies, nasal calcitonin has reduced the pain associated with new spine fractures, although it is now considered preferable to treat osteoporosis with more potent agents and to manage pain separately.

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A randomized trial of A randomized trial of nasal spray salmon calcitoninnasal spray salmon calcitonin in postmenopausal in postmenopausal women with established osteoporosis: the prevent recurrence of women with established osteoporosis: the prevent recurrence of

osteoporotic fractures study. PROOF Study Group.osteoporotic fractures study. PROOF Study Group.

PURPOSE: We conducted a 5-year, double-blind, randomized, placebo-controlled study to determine whether salmon calcitonin nasal spray reduced the risk of new vertebral fractures in postmenopausal women with osteoporosis.SUBJECTS AND METHODS: A total of 1,255 postmenopausal women with established osteoporosis were randomly assigned to receive salmon calcitonin nasal spray (100, 200, or 400 IU) or placebo daily. All participants received elemental Ca (1,000 mg) and vit D (400 IU) daily. Vertebral fractures were assessed with lateral radiographs of the spine. The primary efficacy endpoint was the risk of new vertebral fractures in the salmon calcitonin nasal spray 200-IU group compared with the placebo group.

Am J Med. 2000 Sep;109(4):267-76.

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RESULTS: During 5 years, 1,108 participants had at least one follow-up radiograph. A total of 783 women completed 3 years of Tx, and 511 completed 5 years. The 200-IU dose of salmon calcitonin nasal spray significantly reduced the risk of new vertebral fractures by 33% compared with placebo [200 IU: 51 of 287, placebo: 70 of 270, relative risk (RR) = 0.67, 95% confidence interval (CI): 0.47- to 0.97, P = 0.03]. In the 817 women with one to five prevalent vertebral fractures at enrollment, the risk was reduced by 36% (RR = 0.64, 95% CI: 0.43- to 0.96, P = 0.03). The reductions in vertebral fractures in the 100-IU (RR = 0.85, 95% CI: 0.60- to 1.21) and the 400-IU (RR = 0.84, 95% CI: 0.59- to 1.18) groups were not significantly different from placebo. Lumbar spine BMD increased significantly from baseline (1% to 1. 5%, P<0.01) in all active Tx groups. Bone turnover was inhibited, as shown by suppression of serum type-I collagen cross-linked telopeptide (C-telopeptide) by 12% in the 200-IU group (P <0.01) and by 14% in the 400-IU group (P<0.01) as compared with placebo.CONCLUSION: Salmon calcitonin nasal spray at a dose of 200 IU daily significantly reduces the risk of new vertebral fractures in PMO.

Am J Med. 2000 Sep;109(4):267-76.

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  Strontium Ranelate Strontium Ranelate

Strontium ranelate is orally administered and stimulates Ca uptake in bone while inhibiting bone resorption. In a randomized trial in PMO, daily strontium ranelate reduced the risk of vertebral fracture by 40 %. However, a significant reduction in nonvertebral fracture was observed only in a post hoc analysis of a small subgroup of women. This drug was recently approved by European regulatory agencies, but it is not currently approved by FDA.

HLJ

Anabolic Agents (1)Anabolic Agents (1)The prototypical anabolic drug is sodium fluoride, which was widely used in the 1970s and 1980s because of its ability to stimulate the formation of new bone. However, a randomized trial in 1990 established that despite dramatic increases in BMD, the risk of nonvertebral fracture actually increased with the use of fluoride. In 2002, synthetic PTH (1–34) (teriparatide) was the first anabolic agent approved by FDA for PMO. Unlike antiresorptive agents, PTH stimulates bone remodeling by increasing bone formation. In a large randomized trial involving postmenopausal severe osteoporosis, 20 µg of PTH per day administered S.C. markedly increased BMD and reduced vertebral and nonvertebral fractures by more than 50 %. However, the trial was stopped after 20 months because of concern about the development of osteosarcoma in rats treated with high doses of PTH (1–34).

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Effect of Effect of PTH (1-34)PTH (1-34) on Fractures and BMD in PMO on Fractures and BMD in PMO

Background Once-daily injections of PTH or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown. Methods We randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 µg of PTH (1-34) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study (median duration of observation, 21 months) and performed serial measurements of bone mass by DEXA.

N Engl J Med 2001;344:1434-1441.

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Results New vertebral fractures occurred in 14 % women in the placebo group and in 5 % and 4 %, respectively, of the women in the 20-µg and 40-µg PTH groups; the respective relative risks of fracture in the 20-µg and 40-µg groups, as compared with the placebo group, were 0.35 and 0.31 (95 % confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6 % women in the placebo group and in 3 % of those in each PTH group (relative risk, 0.47 and 0.46, respectively [95 % confidence intervals, 0.25 to 0.88 and 0.25 to 0.86]). As compared with placebo, the 20-µg and 40-µg doses of PTH increased BMD by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-µg dose decreased BMD at the shaft of the radius by 2 more percentage points. Both doses increased total-body BMD by 2 to 4 more percentage points than did placebo. PTH had only minor side effects (occasional nausea and headache). Conclusions Tx of PMO with PTH (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body BMD; and is well tolerated. The 40-µg dose increased BMD more than the 20-µg dose but had similar effects on the risk of fracture and was more likely to have side effects.

N Engl J Med 2001;344:1434-1441.

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Anabolic Agents ( 2)Anabolic Agents ( 2)

As a result, a "black-box" warning was added to the teriparatide label. However, retrospective studies have found no association between osteosarcoma and primary or secondary hyperparathyroidism in humans, and no cases of osteosarcoma have been reported in the more than 200,000 p'ts treated with PTH. The current recommendation is that PTH therapy should be limited to persons with moderate-to-severe osteoporosis and that the duration of therapy should not exceed two years. PTH (1–34) is well tolerated, although mild but asymptomatic hypercalcemia (i.e., a serum Ca level between 10.5 and 11.0 mg/dl [2.6 and 2.8 mmol/l]) can occur rarely. Cost and the requirement of subcutaneous administration are major limiting factors.

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Combination Therapy Combination Therapy

Although studies have suggested that combining antiresorptive agents may slightly increase BMD as compared with monotherapy, there are no data to indicate that combination therapies are superior for reducing the risk of fracture. There is also no evidence that combining PTH with an antiresorptive drug results in additive or synergistic effects, but concurrent use of cyclic PTH (i.e., daily parathyroid for 3 months followed by no Tx for 3 months for a period of 15 months) with alendronate may be just as effective as daily PTH with alendronate. Nevertheless, bone loss will occur after the discontinuation of PTH, but it can be prevented if this therapy is followed by Tx with an antiresorptive drug such as alendronate.

HLJ

Areas of Uncertainty (1)Areas of Uncertainty (1) The optimal timing and type of preventive therapy are still not clearly defined. Many postmenopausal women have T scores between –1.0 and –2.5 but no other risk factors.Postmenopausal hormone-replacement therapy, once considered the best preventive approach for these women, is no longer recommended in light of the associated risks reported in the Women's Health Initiative trial. Bisphosphonates prevent bone loss in women with osteopenia and can be used as prophylaxis, but cost-effectiveness and concerns about the effects on skeletal mineralization over decades may be limiting factors. Studies such as the extension of the Fracture Intervention Trial (evaluating alendronate) have provided some reassurance with regard to long-term use.

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Areas of Uncertainty (2)Areas of Uncertainty (2)Also uncertain is the appropriate care for p'ts who continue to have fractures despite aggressive pharmacologic intervention. Whether new agents such as the synthetic Ab to the receptor activator of nuclear factor- B ligand (AMG 162) or strontium ranelate will be effective in preventing new fractures in such p'ts needs to be tested. Finally, controversy persists about the use of vertebroplasty or kyphoplasty, procedures that introduce material to expand compressed vertebrae and reduce the pain associated with new fractures. Both the absence of randomized, placebo-controlled trials and concerns about the mechanical strength of adjacent vertebrae after these procedures preclude making recommendations for their use.

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(Guidelines)(Guidelines)

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Summary and Recommendations (1)Summary and Recommendations (1)

A careful Hx taking and P.E. that address risk factors for or signs of osteoporosis (particularly previous fragility fractures, height loss, or both, as well as possible secondary causes of bone loss) combined with measurement of BMD should guide therapeutic decisions. Given the high prevalence of low levels of 25(OH) Vit D in women with osteoporosis, measurement of a serum 25(OH) Vit D level by a reliable laboratory is reasonable.

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Summary and Recommendations (2)Summary and Recommendations (2)Tx plans for the woman in the vignette should include Ca supplementation to a level of at least 1200 mg/d and 800 IU of Vit D, as well as pharmacologic therapy. I would start with an oral bisphosphonate (alendronate or risedronate) once weekly or ibandronate once monthly, given the documented reductions in the incidence of hip and vertebral fracture with these agents. Alternatively, one could consider PTH (1–34) for two years if a p't cannot tolerate a bisphosphonate or has had multiple fractures, although with this regimen, cost and compliance need to be taken into consideration.Irrespective of the choice of therapy, careful follow-up, with attention to pain, lifestyle, and risk factors for future fracture, is necessary.

HLJ

須靠醫師 預防骨鬆 補品無助須靠醫師 預防骨鬆 補品無助 預防或治療骨質疏鬆症，你做對了嗎？醫師指出，國人最愛的「補骨食品」：如維骨力、固樂沙敏、阿鈣、綜合維他命、深海魚油、維他命Ｅ及Ｃ、骨頭湯等，其實對於骨鬆症並無太大的幫助。 中華民國骨質疏鬆症學會理事長蔡克嵩表示，骨質疏鬆症是很危險的疾病，易導致骨折，若大腿骨骨折，六十五歲以上男性一年死亡率高達二二％、同年齡女性一年死亡率也達一五％，相當於末期乳癌的死亡率。蔡克嵩表示，骨鬆症的因素包括：種族、遺傳、體重和飲食等，遺傳占很重要的比例，若父母都有骨鬆病史，子女有骨鬆的機率是一般人的四倍；若父母僅一方有骨鬆，則子女罹患率比一般人多出兩倍。

2005.09.03 　 中國時報

HLJ

根據中華民國骨質疏鬆症學會和美商默沙東藥廠共同進行的問卷調查，國人常以為單純增加鈣質攝取量、或服用維骨力（成分為葡萄糖胺）就可以治療骨鬆症。但蔡克嵩表示，葡萄糖胺只是一種關節軟骨基質的補充成分，對軟骨好，但對於骨頭並沒有幫助，因此和骨鬆症無關。每天吃鈣片，也不見得可預防骨鬆症。蔡克嵩建議，無論男女，只要五十歲以上就要密切注意骨鬆症的發生，定期接受骨質密度檢測，必要時依據醫師的指示服用藥物，配合飲食和運動，才是預防及治療骨鬆症的不二法門。

2005.09.03 　 中國時報

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謝謝聆聽 請多指教謝謝聆聽 請多指教