A 67 years old female patient is presented with low bone mineral density and she is unable to tolerate a biphosphonate. The possible reason she is unable to tolerate a biphosphonate is due to severe gastrointestinal disturbances that is associated with biphosphonate even when administration was followed correctly. Low bone mineral density (BMD) is a clinical issue which affects many women, as they approach middle-age and post-menopause.1 The World Health Organization (WHO) definition of osteoporosis is based on the T-score, which is the number of standard deviation below the mean BMD of a healthy, young (20- to 29-year-old), same sex and same race reference population. Normal BMD is a T-score of -1 or above, osteopenia is a T-score of -1 to -2.4, osteoporosis is a T-score at or below -2.5, and severe osteoporosis is a T-score below -2.5 for patients with fragility fracture.1 It is estimated that 40% of all post-menopausal Caucasian women have declined bone mineral density of which a proportion from these women have high risk of developing osteoporosis eventually.1
Mortality and Morbidity
Osteoporosis is a bone disorder with characteristics of compromised bone microstructure and it predisposes individuals to an increased fracture risk. Low BMD is a major characteristic of osteoporosis, which occur when the rate of bone resorption exceed bone formation. There is a strong inverse correlation between BMD and the tendency of bone fracture and hence BMD is the primary determinant of susceptibility to fracture in women without fractures- with a relative risk of 2.6 for every 1 standard deviation decline in BMD.1 In addition to a low BMD, aging causes age-related menopausal osteoporosis and male osteoporosis, from 2% (50 year-old) rising to approximately 25% (80 year-old).1
Fragility fracture is the most clinically significant physical outcome in osteoporosis which is often asymptomatic until a fracture occurs.2Osteoporotic fractures are susceptible to occur at sites of low BMD and are usually worsened by a fall or injury. It is caused by a force that would not cause a normal bone to fracture or a fall from a standing level or less. The clinical risk factor for osteoporosis fractures are having low body weight, oral corticosteroid treatment for more than 3 months, smoking; and a history of having a fracture as an adult, or in a first degree relative. Annually, there are 180000 osteoporosis-related fragility fracture occurred in England and Wales. Of these, 25000 are vertebral fractures, 41000 are wrist fracture and 70000 are hip fracture.26
Hip fractures considered to be the most serious complication of osteoporosis, are associated with 12 to 20% increased risk of mortality within one year following the fracture.2 Most patients never regain their normal mobility, unable to perform daily activity and thus loss of independance.4 Generally, a height reduction of more than 15 to 20% is an indication of a new vertebral (spinal) fracture. The adverse effect of vertebral fractures includes gastrointestinal problems, prolonged disability, acute and chronic back pain, deformity, crowding of internal organs; decreased pulmonary function and consequently having breathing difficulties.5 Vertebral fractures are also related with increased mortality of approximately 4-fold. 4 Fractures at the hip, vertebral and wrist increased the tendency of subsequent non-vertebral fractures.5
Treatment Options: Management of Osteoporosis
The desired outcome of treating low bone mineral density (BMD) is to prevent the occurrence of vertebral- and non-vertebral fractures in patients with or without a prevalent osteoporosis-related fracture, to prevent bone loss, and to delay the progression of the patient's condition with prevalent fractures.4 Measurement of BMD and assessment of clinical risk factor are important in deciding the treatment intervention. Both non-pharmacological and pharmacological intervention should be considered in the treatment options. Pharmacological intervention was proven to reduce the estimated 10-year risk of osteoporotic fracture from 8 to 4% in postmenopausal women with T-score of -1.5 and below.22
Diet and lifestyle modification have been implicated in the prevention of fractures in low bone mineral density patients.17,18 Regular weight bearing aerobic and physical exercise may reduces the risk of falling in the elderly by sustaining bone mineral density and strengthen muscles.18 Calcium supplements of 0.5-1 gram daily and low dose of vitamin D (800 IU daily) lower the incidence of hip fracture in elderly women.17 Clinical trials of biphosphonates, raloxifene, hormone replacement therapy strontium ranelate and calcitonin have often been assessed in combination with calcium and vitamin D supplementation.6,10,16 Hence, calcium and vitamin D supplements are required for optimal bone mass in osteoporosis patients.
All biphosphonates are able to inhibit bone resorption and preserve the bone quality by modifying the activation and function of osteoclast.4 Biochemical rate of bone turnover were demonstrated to decline to the normal premenopausal range in treatment with biphosphonates. They appeared to significantly increase bone mineral density (BMD) thus, strengthening the bone. All biphosphonate become incorporated to the skeletal resulting in long biological half life for up to 10 years.
Cyclical etidronate and alendronate have been shown to be effective in reducing the incidence of vertebral fractures in patients with postmenopausal osteoporosis.6,7 Studies reported that alendronate 10mg daily reduced significantly by approximately 50% the risk of new vertebral fracture and that of non-vertebral fractures by 31%.7 Cyclical etidronate (400mg/day) up to seven years increased the vertebral BMD by 1.8% (year 4) and 2.2% (year 7) compared to baseline at year 0.6 Trials with the treatment of risedronate 5mg daily or 35mg weekly also showed similar results as etidronate and alendronate. 9
Mild gastrointestinal (GI) adverse effects have been reported with the use of all biphosphontes.6,7,9 Biphosphonates given orally can induce nausea, heartburn, vomiting and increased incidence of esophageal ulcers, bleeding events and perforation.7 A few cases with severe oesophagitis have been reported with oral alendronate.7 A controlled study in the Netherlands reported that 10% of patients given alendronate will show GI intolerance in daily practice usually occur within the first 4 weeks of therapy.
In summary, biphosphonates are potent anti-resorptive agents for the prevention and treatment of postmenopausal women with osteoporosis. They have excellent safety profile and have long retention time in the bone. Treatment appeared to sustained high level of BMD in patients at least 2 years after stopping and continuation of therapy showed increased in BMD. However, they have complicated instructions for administration (with a full glass of water and remain upright in position for a period of time thereafter) due to its poor oral bioavailability (1% to 5%). Some patient might be intolerant to biphosphonate due to potential GI side-effects and complex way of administration.
Selective Estrogen Receptor Modulators (SERMS)
SERMS are drugs that mimic estrogen agonist in some tissues and act as antagonist in others.4 They induce estrogen-like effect, which induces optimal effect on bone and lipid metabolism but minimizes the adverse effects on the uterus and breast.
In the MORE study, Raloxifene therapy (60mg or 120mg daily) was given to 6828 postmenopausal osteoporosis patients, in both with and without prior fractures at baseline. Results from the 3 year study showed that raloxifene reduce the incidence of vertebral fracture in both treatment group by a relative risk (RR) of 0.7 and 0.5 respectively. 10 However, there is no significant evidence showing a decreased incidence of non-vertebral fractures. Raloxifene 60mg/day treated patients had a significant increased in bone mineral density (BMD) at the femoral neck by 2.1% and at the spine by 2.6% (both treatment p<0.001). Nevertheless, the extent of raloxifene reducing spine fracture, increasing vertebral and hip BMD is lesser than biphosphonates.4, 10
The advantage of raloxifene compared to estrogen therapy is that it reduces serum cholesterol level without increases the risk of breast and uterus cancer.10 However, the hot flashes and muscle cramps were often reported in the treated women. The most serious adverse effect from the use of raloxifene is the increased risk of venous thromboembolic events by three-folds, with a result comparable to what has been reported with hormone replacement therapy. In terms of its safety profile, the dual action and tissue specificity of raloxifene enhance the value of this drug, making it superior over hormone replacement therapy for the prevention and treatment of postmenopausal women with osteoporosis.4
Strontium ranelate is a divalent strontium salt of ranelic acid and it has the ability to stimulate bone formation and reduces bone resorption at all stages of osteoporosis.4 The PREVOS study demonstrated that treatment with 1 gram daily of SR can stop bone loss in early postmenopausal non-osteoporotic female patients. Result from the two year study showed that spinal bone mineral density (BMD) was increased by 2.8% yearly.11
In another study (STRATOS), SR 2 gram daily in the treatment of established osteoporosis patients showed that there was a significant increase in the spinal BMD of 7.3% annually and there was a significant reduction in the incidence of vertebral fracture (relative risk reduction[RR] = 0.56).12 It is also effective in the treatment of osteopenia patients with a significant RR of spinal fracture in patient with and without a prevalent fracture by RR=41% and RR=38% respectively.23 However, there is a need for evidence in the efficacy of SR treatment in the prevention of hip fracture as current trial did not show a significant risk reduction. In general, mild and transient side-effects such as severe allergic reactions, nausea and diarrhea were reported. A serious adverse event related to this treatment is venous thromboembolism and pulmonary embolism.4 From the overall data, SR is well tolerated, able to sustain an increase level of BMD and lower the risk of spinal fracture in long term treatment. Hence, it can be used in the prevention of bone loss in postmenopausal women with or without osteoporosis.
Hormone replacement therapy (HRT)
Estrogen therapy and combined estrogen-progestin hormone replacement therapy (HRT) were shown to lower spinal, non-spinal osteoporosis fractures and increase bone mineral density in a clinical trial.15 Result is comparable to those seen with biphosphonate treatment. However, the long term use of estrogen therapy increases the incidence of breast cancer, thromboembolism, myocardial infarction, coronary heart disease, stroke and gall bladder disease. Hence, the risk of long term estrogen therapy outweighs the potential bone benefits. When the therapy is discontinued, bone loss accelerates and fracture protection is lost. Therefore, HRT is only indicated for short term therapy of severe menopausal symptoms in women.
Calcitonin is produced from the thyroid gland when serum calcium concentration is increased.4 Salmon calcitonin is used clinically because it has higher half life and is more potent than mammalian calcitonin. In a study, intranasal calcitonin 200 IU daily was shown to lower the risk of spinal fractures by 25 to 35%.16 It appears to delay vertebral bone loss and significantly increased spine BMD by 1-1.5% compared from the baseline (P=0.03) in postmenopausal women but there is no evidence of protection against hip bone loss. The additional benefit for from calcitonin is pain relief from acute fracture. Although nasal calcitonin is one of the options for the treatment and prevention of postmenopausal bone loss, more extensive research on the effectiveness of calcitonin on spinal and hip BMD and fracture risk is required before its role can be compared to biphosphonates.
Parathyroid Hormone (Teriparatide)
Parathyroid hormone (PTH) regulates serum calcium concentration and the rate of bone remodeling turnover13. The physiological action of parathyroid hormone is to sustain optimal serum calcium level and enhance calcium absorption from the gut. Teriparatide, a recombinant product (1–34 amino acid fragments in PTH), is an effective bone forming agent. Teriparatide accelerate osteoblast formation and its activity, accelerating bone formation. A recent multinational study over 21 months, reported that the treatment with teriparatide (40 micrograms once daily) reduced the risk of spinal- and non-spinal-fractures, with a relative risk reduction of 65% and 50% respectively13. The study was done in postmenopausal women who had at least one prevalent spinal fracture prior the treatment. Result also showed that there is a significant gain of bone mineral density at most skeletal sites. Teriparatide therapy occasionally induces headache, nausea, arthralgia and dose dependant hypercalcaemia in a minority of patient. Mild discomfort at injection site has also been reported in treated women.
A study was done to compare the efficacy of 40 µg teriparatide to 10 mg alendronate (a biphosphonate) in osteoporotic postmenopausal women.14 At duration of 3 months, teriparatide increased vertebral BMD significantly more than did alendronate by 12.2% versus 5.6%. Treatment with teriparatide patients have a significantly lower risk of non-spinal fracture by 4.1% compared to patients treated with alendronate (P < 0.05). However, higher incidence of leg cramps were reported, whereas the frequency of new or worsen back pain is lesser compared to alendronate group. In summary, teriparatide was shown to increase BMD at most skeletal sites and decreased non-spinal fractures more than alendronate. Hence, teriparatide is a potent anabolic agent for the treatment of severe osteoporosis, with the ability to reverse osteoporosis and reduce fracture risk. Overall, it is well tolerated and its safety profile is acceptable over 2 to 3 years of therapy.4 However, long term safety profile is yet to be established because of the initiation of osteosarcoma in a rat model of carcinogenicity.
Treatment Recommendation: Primary Prevention of Osteoporosis-related fractures
The incidence of fractures in the elderly is strongly related with bone fragility and bone mineral density (BMD). Screening of BMD in individuals who are more than 65 years old and the assessment of clinical risk factors are recommended as screening helps identify patients whose risk of fracture is sufficiently great that treatment is considered to be cost-effective.4 Hence, knowing that this patient has low BMD, the desired treatment outcome for her is to prevent bone loss, to strengthen bone architecture, and reduce fracture risk by pharmacological and non-pharmacological intervention.
The patient should be counseled on lifestyle measurement including physical exercise, calcium supplementation, and vitamin D supplementation. A meta-analysis of fifteen trials demonstrated that calcium supplementation of 500-2000 milligram per day had a significant increased of BMD by 2.05% over more than 2 years, resulting in reduction in vertebral and hip fractures in postmenopausal women.19 Likewise, vitamin D supplementation of 300 to 2000 IU daily in postmenopausal women, lowered the incidence of spinal fractures and non-spinal fractures with relative risk reduction of 0.63 and 0.67 respectively.20 It was shown that a person over 65 years of age can only reach serum 10 microgram (400 IU) of vitamin D by supplementation. Adequate level of calcium and vitamin D ensures optimal pharmacological treatment as shown in many clinical trials where supplementation of both calcium and/or vitamin D were given.6,7,9,10,11,13,14,16
Resistance exercise, weight bearing physical activity and aerobic were all beneficial on the vertebral BMD and reduce the risk of falling in the elderly.27 Weight bearing exercise was showed to increase BMD significantly by 0.006 g/cm at the lumbar spinal of postmenopausal women.4 Walking was shown to be effective with a weighted mean difference (WMD) of percentage changes of 1.31 in the BMD of the spine and the hip (0.92). Given that excessive caffeine consumption increases calcium secretion, caffeine intake should ideally be limited to 2 serving per day.4Additionally, smoking cessation can promote peak bone mass, minimize bone loss and ultimately reduce incidence of fracture.4 Hence, the patient should have a dietary intake of 1000 mg calcium daily (either by supplement or dietary); supplementation of vitamin D (400 to 800 IU daily) and have regular exercise such as walking or involve in moderate resistance training program.
For the pharmacological primary prevention of osteoporosis, NICE guideline recommends the use of biphosphonates (alendronate, etidronate, residronate), raloxifene and strontium ranelate.26 Since the patient is unable to tolerate biphosphonates, so raloxifene or strontium ranelate can be considered as the alternative treatment. Both raloxifene and strontium ranelate were proven to increase bone mineral density, strengthen bone integrity and ultimately reduce the risk of non-vertebral and vertebral fractures. 10, 11, 12 However, raloxifene increases the risk of venous thromboembolism by three fold so this reduce its value as a drug for long term treatment.
A study showed that the long term use of raloxifene is only cost-effective in treating women with increased risk of spinal fracture (with a prevalent fracture) and at the age of at least 70 years old and a above 21 Result from the analysis demonstrated that the cost per quality adjusted life-years (QALY) for women without prevalent fracture was almost two-folds compare to the cost per QALY of women with at least one fracture (￡18,000 vs. ￡10,000 at age 50). Hence, considering the cost-effectiveness with raloxifene compare to no treatment, it is only effective in women above 70 years old with osteoporosis and with a prior fracture.
Strotium ranelate(SR) 2 gram daily is the recommended drug for this patient especially for long term treatment.24 The SOTI trial demonstrated that strontium ranelate reduced the incidence of spinal fractures by 49% after a year and by 41% over 3 years of the therapy in postmenopausal women with osteoporosis.24 PREVOS study showed that SR 1g/day increased the BMD of the kneck and hip in postmenopausal osteoposoris women.11 In addition, the STRATOS study showed that SR prevented bone loss and increased spinal BMD by 7.3% in established osteoporosis patient, whereas another study proved that SR is effective in reducing vertebral fracture risk in osteopenia patient, with and without a prevalent fracture.12,23There was a reduced incidence of back ache and loss in height in treated patients.
Overall, SR is well tolerated with comparable adverse effect rates in both treated and placebo groups except that nausea and diarrhea were reported more often within the first 3 months, and thromboembolism and pulmonary embolism within the first year.24 SR increases BMD at all skeletal site significantly whereas raloxifene needed more clinical evidence for the effectiveness on hip BMD.11,12 A study showed that the long-term treatment with strontium ranelate in postmenopausal women with osteoporosis is cost-effective over 5 years compared to no treatment although it is less cost-effective compared to biphosphonate (alendronate).25 Hence, in this case, SR is the preferred choice for its efficacy, safety-profile and cost-effectiveness for long term benefits of prevention of bone loss and fractures.