Osteoporosis Is A Systemic Skeletal Disorder Case Study Biology Essay

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In the scenario given, a 75 year old female patient with low bone mineral density (BMD) who is unable to tolerate a biphosphonate, has suffered more than 2 fractures. The assumed diagnosis is osteoporosis. According to World Health Organization (WHO), osteoporosis is defined by a T-score of -2.5 standard deviations (SD) or lower of a young adult mean bone mineral density obtained from dual-energy X-ray absorptiometry (DXA) scanning. Despite this, according to National Institute for Health and Clinical Excellence (NICE) guideline, assumed diagnosis of osteoporosis can be done in women aged 75 years or above without a T-score(1).

Osteoporosis is a systemic skeletal disorder in which the bone is suffered from mass loss due to increase bone resorption by osteoclast relative to bone formation by osteoblast. It is characterized by alteration of bone micro-architecture, low bone mineral density, decreased bone strength and increased fragility fracture risk. Osteoporosis is an age-related clinical condition with gradual bone mass loss starts at the forties or fifties (2). It affects both sexes but more common in post-menopausal women with the risk increases with age from around 2% at 50 years to 25% at 80 years (1).

Osteoporotic fracture is the major clinical outcome of osteoporosis. In UK, the risk of suffering a fracture among the women and men 50 years and above are 50% and 20% respectively (3). Osteoporotic fracture is a fracture caused by a trauma which would otherwise do not result in fracture in normal healthy bone. It is often associated with hip, wrist or spinal bones (2). Osteoporosis leaves great impacts in the physical, psychosocial and financial aspects (4). It causes both mortality and morbidity in the patient. The survival rate of a patient after a fracture is varied according to the part of body involved with hip fracture to be the most serious. 10-20% of women die within the first year after a hip fracture. Spinal fracture is also increases mortality rate that extends beyond the first year of fracture. This could be attributed to the fracture or the subsequent fracture-related development of cardiovascular, cancer and pulmonary disease (5, 6).

Besides, osteoporotic fracture causes significant disability and reduce patient's quality of life. Following a hip fracture, approximately one-third of the patient becomes totally dependent. Although less likely to cause disability, spinal fracture affects patient's daily activities and causes backache, height loss and vertebral deformity. Even for a milder condition like wrist fracture, patient's activities are restricted to an extended period as one in two of the patients has poor functional outcome at 6 months. Apart from physical functionality, patient's psychological well-being is also affected as depression, low self-esteem and anxiety are reported (5).

From the financial perspective, osteoporosis causes substantial economic lost and increases social burden. In 1998, approximately £727 million was spent on the treatment of osteoporotic fracture among the female population in UK which covered both the hospital health care and social care cost (7). The cost has been predicted to increase to more than £2 billion by 2020 due to the aging population (3). Apart from this direct medical cost, there is also a loss in the productivity due to absence from work and premature death.

Summarizing the fact that osteoporosis fracture can lead to serious consequences and the woman in the scenario given is at a high risk of further fracture due to her high age and prior fractures which associate with a 86% higher risk of any further fracture, pharmacological intervention should be started promptly in this case (8).

Treatment Options

The main aim of osteoporosis treatment is to prevent osteoporotic fracture. Currently, there are a number of licensed therapeutic agents available in UK for the treatment which can be classified according to their mode of action. They are anti-resorptive agents include biphosphonates, raloxifene, calcitonin and hormone replacement therapy (HRT) which suppress bone resorption, result in bone turnover suppresion, bone anabolic agent like parathyroid hormone peptides which stimulate bone formation, result in stimulated bone turnover and dual action bone agent like strontium ranelate which uncoupled the bone remodeling, exerts both anti-resorption and bone formation effect (2, 9).

Biphosphonates are the current first line therapy for secondary prevention of post-menopausal osteoporotic fracture (1). However, as the patient in this case is unable to tolerate biphosphonates, an alternative therapy should be sought. According to BNF 59, strontium ranelate, teriparatide or raloxifene can be considered as an alternative therapy for osteoporosis in postmenopausal women if biphosphonates are intolerated (9).

Strontium ranelate

Strontium ranelate (SnR), one of the treatment option available is a compound consists of two strontium atoms and a ranelic acid molecule. SnR is able to uncoupled bone remodeling, exert both anti-resorption and anabolic action on the bone, and hence produce a net bone formation. From In vitro and animal model studies, SnR has been found to inhibit the proliferation and activity of osteoclasts but promote the proliferation and activity of osteoblasts. This is further shown in clinical trials where SnR-treated patients were found to have a raised serum bone-specific alkaline phosphatase indicating bone formation and a decrease of serum C telopeptide cross-links of type I collagen indicating a decrease in bone degradation (10).

The clinical efficacy of SnR on osteoporosis and hence prevention of vertebral, non-vertebral and hip fracture has been proved in several studies. In Spinal Osteoporosis Therapeutic Intervention (SOTI), 3 years of 2g SnR treatment was found to be able to decrease the new vertebral fracture risk by 41% and a 38% decrease in the symptomatic vertebral fracture risk compared to the placebo group (11). This trend continued when the treatment was extended to 4th year (12). On the other hand, the clinical efficacy of SnR on non-vertebral fracture has also been shown in Treatment Of Peripheral Osteoporosis (TROPOS) study with a 16% decrease in total non-vertebral fracture risk and a 19% decrease in fracture risk involving main fragility fracture parts like hip, wrist, pelvis and sacrum, ribs and sternum, clavicle and humerus after 3 years of 2g SnR treatment compared to placebo. From the aspect of hip fracture, a 15% decrease in risk was noted in the treated group, however this was not statistical significant. A post-hoc analysis in this study showed a 36% decrease in the hip fracture risk among the high risk patients who are defined as above 74-year-old with a t-score of ≤ -3 when compared to the placebo group (13). This trend was found to maintain throughout 5 years of therapy (14).

Apart from the direct clinical outcome in reducing fracture risk, SnR has also been consistently found to increase BMD in femoral neck, total hip and lumbar spine in several studies although part of this increment can be attributed to the enhanced x-ray absorption ability of strontium compared to calcium (12, 14-16). The benefit of a gain in femoral neck and total hip's BMD is projected in a decrease in the non-vertebral fracture risk (17). Besides increase in BMD, SnR is also able to improve bone tissue quality which collaboratively enhance the bone biomechanical strength, and hence reduces fracture risk (10).

The consistency of SnR efficacy profile has been determined from a pooled data of these two studies. It was found that SnR is beneficial to a wide range of patient with a promising long-term efficacy. This is due to the fact that the efficacy of SnR on vertebral fracture prevention was not varied according to baseline BMD, body mass index (BMI), prevalent fractures, family history of osteoporosis, smoking habit and age. Moreover, it is also effective to elderly women age 80-100 and postmenopausal women with osteopenia (18). The efficacy of SnR was sustained in subjects treated for up to 8 years (19). Besides clinical benefit, SnR was found to provide additional beneficial effect in the aspect of patient's quality of life by improving patient's mobility, emotional state and reducing pain (12).

In terms of safety, both SnR-treated and placebo group shared a common adverse event record with side effects include nausea, diarrhea, headache, dermatitis and eczema were most frequently reported during the first three month of therapy (11, 13, 15). Despite this, SnR-treated group was identified with a 0.3% greater risk of venous thromboembolism (VTE) compared to placebo group. Besides, it was also associated with rare cases of hypersensitivity syndrome which requires termination of treatment (20).The safety profile of SnR was found to be consistent over the 8 years of treatment and at all age groups (15).


The second treatment option is raloxifene which is a non-steroidal selective eostrogen receptor modulator (SERM) exerting an oestrogen-like effect in the bone and antagonize the effect of oestrogen in the reproductive tissues (4). As oestrogen playing a role in inhibiting osteoclast activity, low level of oestrogen in post-menopausal women leads to a massive bone lose due to lack of this inhibition effect. Hence, the aim of SERM treatment is to utilize the beneficial effects of oestrogen on bone while at the mean time minimizes its effects on the breast and endometrium tissue to avoid side effects (1).

Raloxifene is effective in preventing osteoporotic vertebral fracture. In Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a three-year raloxifene treatment with a daily dose of 60mg and 120mg successfully decreased the spinal fracture risk among the osteoporotic post-menopausal women by 30% and 50% respectively (21). From Continuing Outcomes Relevant to Evista [CORE] study, a 39% decrease in new vertebral fracture risk was also noted in year 4 alone with the treatment of 60mg raloxifene (22). The finding from Raloxifene Use for The Heart (RUTH) trial which was 35% reduction in vertebral fracture risk following daily treatment with 60mg raloxifene for a median years of 5.6 again proved the efficacy of raloxifene in preventing vertebral fracture (23).

Besides the benefit in reducing fracture risk, raloxifene also reduces the severity of future vertebral fracture (24). This might attributable to its effect on bone tissue modification as it was found to increase BMD in the femoral neck and spine (25). Besides, it also enhances bone biomechanical strength by suppressing the breakdown of collagen type I in the bone and hence suppressing bone resorption. Despite this, raloxifene did not reduce the non-vertebral fracture risk (21).

Besides the protective effect against osteoporotic fracture, both MORE and RUTH studies found that raloxifene has an additional benefit in reducing the risk of oestrogen-dependent breast cancer (21, 23).

In terms of safety, the main concern regarding the use of raloxifene is VET. A threefold increase in risk was associated with the use of raloxifene compared to placebo group (21). This is parallel with the finding in RUTH study where raloxifene caused an increase in the relative risks of VET by 44% and fatal stroke by 49% (23). Other side effects caused by raloxifene includes hot flushes, leg cramps, influenza-like symptoms, endometrial cavity fluid, peripheral oedema and worsening diabetes (9, 23). The safety profile of raloxifene remained the same throughout 4 years of treatment (22).


The third treatment option, teriparatide is a recombinant fragment of the first 34 amino acids of human parathyroid hormone (hPTH). hPTH modulates both calcium balance and bone remodeling in mammals. While continuous exposure to hPTH leads to bone loss, an intermittent exposure, for example by daily subcutaneous injections with a low dose is in fact results in bone formation due to the increase in osteoblast number and activity (26).

Following bone formation effect, Teriparatide is expected to decrease the risk of fracture. At the licensed dose of 20μg daily given by subcutaneous injection, teriparatide has been found to effectively reduce both vertebral and non-vertebral fracture risk. In a study carried out by Neer et al, the new vertebral fracture risk was decreased by 65% and new non-vertebral fragility fracture risk was decreased by 53% after a mean of 18 months of treatment compared to placebo group (27).

Besides the direct clinical benefit in terms of fracture risk, teriparatide was also found to be able to increase the whole-body BMD, particularly femoral and lumbar BMD. In addition, the bone quality which plays a role in determining the risk of fracture was also improved subsequent to teriparatide treatment. Teriparatide has been found to improve the bone architecture, increasing trabecular bone volume, cortical bone surfaces and thickness (28).

Although the maximum duration of the licensed 20μg teriparatide course is 18 months, its benefit on the protection of fragility fracture sustained after cessation of the treatment. This was shown in the study which continue to monitor the subjects in the Neer et al study for 18 months after the treatment ended. A 41% reduction in the risk of new vertebral fracture was noted. However, there was no significant difference in the new non-vertebral fracture risk between the 20μg teriparatide-treated group and the placebo group (29, 30). Similarly to SnR, teriparatide is useful for a wide range of patient as its anti-vertebral fracture efficacy was not modulated by age, number of prevalent fractures and vertebral bone mineral density (27, 31).

In addition to the clinical benefits, teriparatide was found to reduce the pain suffered by osteoporotic fracture patient during the 12months or 18 months of treatment which subsequently result in the improvement of quality of life as evaluated by the quality of life (QoL) questionnaire of the European Foundation for Osteoporosis (QUALEFFO) (32, 33). However, the benefit was slightly decrease following 6 months after cessation of the therapy (33).

In terms of safety, the most commonly reported side effects in the study carried out by Neer et al were headache, nausea, dizziness and leg cramp which are dose-dependent. Besides, mild hypercalcemia was also reported in the 20μg teriparatide-treated group. Although parathyroid hormone is associated with osteosarcomas in rats in one of the study, this is not found in humans as several studies have proved that it does not increase the incidence of bone cancer in the teriparatide-treated patients. Furthermore, teriparatide was found non-mutagenic and non-genotoxic in the standard tests (27). Hence, this is not a reason for excluding the use of teriparatide in osteoporosis treatment. The long-term safety of teriparatide has been investigated with no serious adverse event was reported up to 30 months after discontinuation of the treatment (29, 30). The safety of teriparatide is promising at all age groups (34).

Recommendation of Treatment

The ideal treatment for osteoporosis should be able to prevent osteoporotic fracture by increasing bone mass and bone strength, improving bone microarchitecture and safe in long term. Hence, in the selection of the therapy, the drug efficacy and safety profile, patient characteristic and preferences and cost-effectiveness of the drug should be taken into consideration. As there is no head-to-head comparison between the efficacy of the drugs, the efficacy of each drug derived from individual study must be analyzed critically recognizing the variation in each studies.

After reviewing all the treatment options stated above, SnR is recommended as the best treatment for the patient in the scenario given. The main reason for this is due to its ability to reduce hip fracture risk which was not found in other agents (13). As hip fracture has high morbidity and mortality rate, this greatly increases the cost-effectiveness of SnR. Although the reduction in the hip fracture risk was not significant in the TROPOS study, the result should not be neglected taking into consideration the large number of subjects (n=5091) involved (13). Besides, the significant result obtained from the post-hoc analysis among the high risk patient is also representative as it is applicable to the patient in the scenario who is also at high risk of osteoporotic fracture (13).

Besides hip fracture, SnR is also found to be effectively reduce the risk of vertebral and nonvertebral fracture (11, 13). As there is no evidence showing raloxifene is effective in reducing the risk of non-vertebral fracture, it is relatively weak as a choice of treatment for the high risk patient in the scenario. Although it is well established that raloxifene is effective in reducing the risk of breast cancer, this advantage is more favourable for younger women (1, 35).

The additional benefit of SnR is its unique action mode which stimulates bone formation and reduces bone resorption simultaneously, hence increases the bone mass in a more physiological way than either anti-resorptive or anabolic agent (10). Anabolic action is important for patient with established osteoporosis to restore the bone strength. Although the bone formation effect was found in the treated subjects in both SOTI and TROPOS trials, there was study suggests the anabolic action of SnR was limited and relatively weak compared to teriparatide (36). However, due to the cost and route of administration of teriparatide, it is preferably reserved for patient with severe osteoporosis or who is unresponsive to anti-resorptive agent (1, 18).

As osteoporosis requires long-term treatment, a drug with long-term efficacy and safety profile is essential. SnR is able to meet this criteria as its efficacy and safety profile have been studied in two 5 years pre-plannned randomized controlled trials which were extended to 8 years among certain subjects (11, 13, 19). As the longest studied drug among the three, SnR provides a more confident result in its long-term efficacy and safety profile. Besides, as the efficacy and safety profile of SnR has been tested on elderly subjects with a mean age of 77 in TROPOS study and the similar result was found in subjects aged 80-100, the result can be confidently applied to the patient in this case who is 75-year-old compared to the findings for other drugs which was done on younger subject population (13, 20).

In term of safety, generally SnR and teriperatide only cause mild side effects (11, 13, 15, 27). However, raloxifene has been proven to cause a threefold greater risk of VTE (21, 23). According to BNF 59, it should be avoided in patient with prolonged immobolisation (9). Although the mobility of the patient in this case is unknown, however, based on her high age and history of more than 2 fractures, she might have a limited mobilization. Hence, raloxifene would not be an appropriate choice for this patient. For SnR, a significant increase in VTE was also found in the pooled data analysis of phase three clinical trials (20). However, as the subjects with VTE history was unbalanced between the treated and placebo group, when the subjects with this history were excluded, there was no significant difference between the two groups in the risk of VTE (20). Besides, there were studies found the risk of VTE was not significantly different between the SR-treated group and group receiving other anti-osteoporotic treatments and non-treated group (37, 38). Since the risk of SnR causes VTE is inconclusive, it is not contraindicated in patient with prolonged immobilization (9). Hence, it can be used in this case where the patient's mobility state is unknown. However, it should be used cautiously and particular attention should be given to possible signs and symptoms of VTE (9).

All three drugs are given on a daily basis with teriparatide is administered subcutaneously and raloxifene and SnR are taken orally. Subcutaneous injection might be present as a less favourable route of administration for patient who is unable to master injection technique or unable to accept taking injection daily. On the other hand, SnR and teriparatide have been found to be able to reduce pain in patients and improve their quality of life (12, 32, 33). Hence, they present a more favourable profile than raloxifene. As these two factors are able to affect patient's compliance to long-term drug therapy and subsequently affects the clinical outcome, they should be taken into consideration in choosing therapy option.

From the aspect of cost, raloxifene is the cheapest drug among the three with a yearly costs of £222.39 to £258.93. The yearly costs of SnR is £333.71 whereas teriparatide is the most expensive drug with a yearly cost of £3544.15. Although not being the cheapest option, SnR results in an incremental cost-effectiveness ratio (ICER) of less than £30000 per quality-adjusted life-year (QALY) gained at 75-year-old patient with a higher t-score, hence lower fracture risk compared to raloxifene and teriparatide (1). This is parallel with the statement above that teriparatide should be reserved for patient with severe osteoporosis and unable to tolerate biphosphonate or SnR (1, 18). Besides, SnR treatment is also considered to be cost-effective compared to no-treatment (35). Since the t-score in this patient is unknown and assuming she has not taken these three drugs before, SnR should be the first choice in this case.

In conjunction with SnR, the patient should be given calcium and vitamin D supplements daily with the dose based on the baseline level and diet intake. This is due to the fact that all the drug efficacy stated above was established in the presence of calcium and vitamin D supplements. Besides, there are evidences show that both calcium and vitamin D supplements reduce the risk of fractures (39).

In conclusion, 2g SnR, preferably taken at bedtime is given once daily for the patient in this scenario with vitamin D and calcium supplements taken at least 2 hours before or after taking SnR (40). This option is also parallel with NICE guideline which recommends SnR as one of the alternative therapy for the secondary prevention of osteoporotic fracture in post-menopausal women who is unable to tolerate biphosphonates (1).