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Review Article
OSTEOPOROSIS: KEY ISSUES IN MANAGEMENT
Ambrish Mithal* and Nidhi Malhotra#
From the Senior Consultant in Endocrinology*, DNB student in Endocrinology#, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India.
Correspondence to: Dr. Ambrish Mithal, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India.
Osteoporosis is a disease characterized by low bone mass with micro architectural deterioration of bone tissueleading to enhance bone fragility. This increases the susceptibility to fracture. Osteoporosis is a major publichealth problem. Hip fractures are the most devastating consequence of osteoporosis. Osteoporosis isessentially an asymptomatic disease. Medical evaluation includes complete history and examination toidentity risk factors, secondary causes of osteoporosis, and secondary complications of fractures. Low bonemass can only be diagnosed by measuring bone mineral density (BMD) by various techniques of which thegold standard is DEXA. Current management strategies include nonpharmacological measures like regularexercise, Calcium and vitamin D rich healthy diet, abstinence from smoking and prevention of falls.
Pharmacological measures include Anticatabolic drugs like Bisphosphonates (Alendronate, Risedronate,Zoledronate). SERMs. Estrogen, Calcitonin, and anabolic drugs like Teriparatide, and Strontium. Correction ofmetabolic abnormalities by judicious use of calcium and vitamin D is desirable before initiating specific drugtreatment. Ralixifene, Estrogen and Strontium are used in mild osteoporosis, Bisphosphonates arerecommended in moderate to severe osteoporosis and Teriparatide use is indicated in severe osteoporosiswith fractures. Calcitonin is used as adjuvant especially for its adjuvant effect.
Key words: Osteoporosis, Hip fracture, DEXA, Bisphosphonates, Teriparatide, Calcium, Vitamin D.
OSTEOPOROSIS is a disease characterized by low bone mass results in fractures which may occur on trivial activities with micro architectural deterioration of bone tissue leading like fall from standing height, lifting heavy objects, sudden to enhance bone fragility. This increases the susceptibility jerks, coughing, sneezing etc. Vertebral fractures may present as severe back pain, loss of height, and spinaldeformities like kyphosis, stooped posture etc. Hip BACKGROUND
fractures are the most serious consequence of (1) Osteoporosis is a major public health problem. There osteoporosis; sometimes the patient falls as a result of the is rapid increase in aging population in India.
spontaneous hip fracture (as opposed to a fall causing the (2) Normally, one out of two women suffer from osteoporosis beyond age 50 and one out of 4 have Medical evaluation includes complete history and examination to identify risk factors, secondary causes of (3) Hip fractures are the most devastating consequence of osteoporosis, and secondary complications of fractures.
osteoporosis (20% mortality, another 25% require life In addition, the patient’s risk of falling should be assessed- time assistance). Recent data suggests that multiple poor vision, overall frail health, unsteady gait, instability, vertebral fractures have major impact on the quality of neurological disorders and the use of sedatives are life, although their overall impact is less than that of Certain laboratory tests are needed in all patients: (4) Although solid data are not yet available, in India the complete blood count, serum calcium, phosphorus, risk may be even higher due to associated nutritional alkaline phosphatase, liver and renal function tests.
Additional laboratory evaluation includes serum PTH, (5) Average osteoporotic fractures occur 10-20 years TSH, 25 hydroxy vitamin D and serum protein earlier in India. Earlier diagnosis and treatment can Diagnosis
CLINICAL EVALUATION
Low bone mass can only be diagnosed by measuring Osteoporosis is essentially an asymptomatic disease. It bone mineral density (BMD) by various techniques, of Apollo Medicine, Vol. 3, No. 2, June 2006 Review Article
markers can distinguish such fast losers from average Table 1. Evaluation of osteoporosis.
losers e.g., bone specific alkaline phosphatase and osteocalcin (bone formation markers) and urinary N-telopeptide, C-telopeptide and PINP (bone resorption markers). These bone turnover markers are suppressed to To rule out secondary causes of bone loss 50% within 3 months of starting antiresorptive therapy.
Hematological disease and malignancy This allows earlier identification of non-responders.
Complete blood count,ESR or CRP,Serum protein However, they can’t be used to diagnose osteoporosis or CURRENT MANAGEMENT STRATEGIES
Metabolic bone diseaseSerum calcium, phosphorus, alkaline phosphatase, (i) Exercise: Regular physical exercise, especially weight bearing and muscle strengthening exercise, delays the physiologic decrease of BMD that occurs with ageing 24 hr urine free cortisol, serum estradiol, testosterone, (Ernst, 1998). One beneficial effect of exercise in the elderly is likely to be the reduction in the risk of fallingthat result from improved muscle strength and co- Chronic renal disease and Malabsorption Serum creatinine, Endomyseal antibodies to excludeceliac sprue (ii) Diet: The nutrients known with certainty to be important are calcium, vitamin D, and protein.
Phosphorus, certain trace minerals (manganese, which the gold standard is DEXA (Dual energy X-ray copper, and zinc), and vitamins C and K, while Absorptiometry). BMD assessment confirms diagnosis, involved in bone health generally, are less certainly detects disease in asymptomatic state, predicts chances of involved in osteoporosis. A well balanced diet future fractures, and is also useful for monitoring response providing 1.2 g of calcium and 800 IU of vitamin D should be recommended for women of all ages.
WHO criterion for diagnosis of osteoporosis is based (iii) Fall prevention: Most fractures other than vertebral on ‘T’ score (Table 2). T score depicts the bone density of fractures are associated with falls. With increasing age, a person when matched to young adult normal bone (which falls become more frequent and the risk of injury from corresponds to peak density of a 30-year-old person).
any single fall also increases. Therefore prevention of ‘Z’ score denotes the bone density of a person when falls is likely to reduce the incidence of fractures in elderly women. Hip protectors should be re- There are factors other than BMD that help in assessing the risk of Osteoporotic factures (Table 3). Five to ten per (iv) Smoking cessation: Smoking increases bone loss. It cent of all menopausal women is fast losers of BMD and also reduces the beneficial effects of postmenopausal hence has a higher risk of fracture. Bone biochemical Table 2: World Health Organisation criterion for the diagnosis of osteoporosis 1994.
A value for BMD that is not more than 1 SD A value for BMD that lies between 1 and 2.5 SD the young adult mean value in the presence Apollo Medicine, Vol. 3, No. 2, June 2006 Review Article
is insufficient to meet either the demands of growth or the TABLE 3: Secondary causes of osteoporosis
drain of cutaneous and excretory losses, resorption will bestimulated by PTH (parathyroid hormone) and bone mass Clinical data: Calcium and vitamin D supplementation reduces bone loss and fractures at all ages especially in elderly. They are, however, usually not used as the sole treatment of osteoporosis, but as essential adjuncts to treatment. The fact that vitamin D deficiency osteomalacia is very common in urban Indians [3], it is necessary to ensure adequate intake of Calcium and vitamin D before Cancer (especially hematological conditions, embarking on any pharmacological therapy for osteo- porosis. Many experts now feel that at least 800 IU of Congenital disorders (osteogenesis imperfecta, vitamin D and 1.2 g of calcium are required daily by every 10. Neurologic disorders (including immobilization and BISPHOSPHONATES
(a) Nitrogen containing compounds Alendronate, Risedronate, Pamidronate, Zoledronate.
Pharmacological approaches
(b) Non-nitrogen containing compounds: Etidronate, According to the latest nomenclature, the anti Osteoporotic drugs have been classified into anti-catabolic Mechanism of action
and anabolic, depending on their effects on boneremodeling and with respect to the mechanisms of fracture They act by binding avidly to mineralized bone surfaces and reduce bone turnover, largely by decreasingactivation frequency and the recruitment of osteoclast Anti-catabolic drugs: These drugs increase the bone precursors, but they also reduce the amount of bone strength by decreasing bone remodeling (less BMUs removed during the resorption phase of the BMU cycle by are formed) that leads to preservation of skeletal either decreasing osteoclast work capacity or by increasing microarchitecture. They reduce the bone turnover largely apoptosis. They should be taken first thing in the morning by decreasing Activation frequency and recruitment of with water, and 30 minutes before the first food, drink or osteoclast precursors. The fracture reduction associated oral medication to be taken that day. Patient should remain with anticatabolic drugs is largely caused by inhibition of upright for at least 30 mins. Bisphosphonates currently in high bone turnover, independent of its effect on preventing ALENDRONATE
Anabolic drugs: These drugs increase the bone strengthby increasing bone mass substantially as a result of an Clinical Data: Alendronate (10 mg/day) after 3 years of overall increase in bone remodeling (more BMUs are treatment produces a vertebral fracture risk reduction of formed) combined with a positive BMU balance (the 47%, non- vertebral (osteoporotic) fracture risk reduction magnitude of the formation phase is more than that of the of 36% and hip fracture risk reduction of 51% (Fracture resorption phase). This results from the combination of intervention trial) [4]. It also reduces bone turnover increased osteoblast function and an inhibition of markers by 50-70%. Once weekly dosing improves patient apoptosis that extends osteoblast life span.
compliance and also pharmacokinetics of the drug.
ANTICATABOLIC DRUGS
Although 10 years of alendronate treatment appears to Calcium and vitamin D
be safe, the optimal duration of treatment has not beenestablished [5].
Supplementary calcium and vitamin D are generally given with other anti catabolic agents as enhancers whose Dose schedule
small, but significant, effects depend mainly on whether The recommended dose of alendronate for prevention of postmenopausal osteoporosis is 5 mg/day or 35 mg/ Mechanism of action: Whenever absorbed calcium intake week and for treatment is 10 mg/day or 70 mg/week. For Apollo Medicine, Vol. 3, No. 2, June 2006 Review Article
treatment of corticosteroid-induced osteoporosis, the to be much more acceptable to patients and could reduce indicated dose is 5 mg/day for men and estrogen replete women and 10mg/day for postmenopausal women.
Dose schedule
RISEDRONATE
Single annual dose of 4 mg is given as an intravenous While first and second generation bisphosphonates are known to have gastrointestinal side effects, Risedronate is In trials of treatment with zoledronic acid for bone metastasis, 9-15% of the patients developed renal It increases BMD by 3-6% and reduces bone turnover by 40-60%. Risedronate (5 mg/day) taken over a period of3 years produces a vertebral fracture risk reduction of 41% IBANDRONATE
and non-vertebral fractures risk reduction of 40% (VERT It recently got FDA approval for its use as a once Dose schedule
Clinical data
The approved dose is 5 mg/d or 35 mg/wk. It seems to Significant reduction in new vertebral fractures in both have better GI tolerability as compared to Alendronate.
treatment arms (62% and 50% respectively, versus According to a recent Gastroenterology study, both placebo), was observed after 3yrs in women with Alendronate and Risedronate have mucosal irritative and established postmenopausal osteoporosis [10]. Both healing impairing effects in the stomach, yet the effect of treatment groups also produced a statistically significant Risedronate was much less pronounced compared to relative risk reduction in clinical vertebral fractures (49% and 48% for daily and intermittent ibandronate, PAMIDRONATE
respectively). The incidence of non-vertebral fractures wasfound to be similar in both ibandronate and placebo It is approved by the FDA for treatment of hyper- calcemia of malignancy and Paget’s disease of bone.
Recently, oral intermittent ibandronate administered Clinical data
once a month was shown to be therapeutically equivalent It has been shown to increase BMD or prevent bone to daily oral regimen thus demonstrating the feasibility loss in patients with post menopausal osteoporosis and of once monthly dosing in the management of post- corticosteroid induced osteoporosis.
Dose schedule
Dose schedule
It is given as an initial dose of 90 mg I/V with It is approved as a once daily oral tablet (2.5 mg/day) subsequent doses of 30 mg every 3rd month.
and also as a once monthly oral tablet in postmenopausalosteoporosis with recommended dosage of 150 mg on the ZOLENDRONATE
same date each month. This drug requires a more It is the most potent bisphosphonate currently available.
prolonged 1 hr fast for adequate absorption as compared Intravenous administration of zolendronate is also to other bisphosphonates. Ibandronate is also the first considered a superior alternative to oral bisphosphonates bisphosphonate with the potential for administration by IV in osteoporosis which are known to carry some limitations injection over 10 to 20 secs without adversely affecting related to long term compliance, gastrointestinal intolerance and poor and variable absorption from ESTROGEN
Estrogen deficiency is associated with an increase in Clinical data
the secretion of cytokines IL-1, IL-6, TNF, M-CSF, RANK At 12 months zoledronic acid regimens were associated Ligand. Increased cytokine activity results in the with deceases of 49 to 52% in serum CTx and deceases of recruitment and activation of more osteoclasts which leads 54 to 65% in serum NTx, increase in lumbar spine bone to increased bone resorption. Estrogen treatment reverses density by 4.3 to 5.1%, femoral neck bone density by 3.1 to 3.5%, with no significant difference among Clinical data
various zoledronic groups. Therefore, administra-tion ofzolendronate at intervals of 6 to 12 months or more is likely In the WHI trial HRT reduced the risk of hip and Apollo Medicine, Vol. 3, No. 2, June 2006 Review Article
vertebral fractures by 34% and of all other osteoporotic Dose schedule
fractures by 24%. This reduction was nominally significant Raloxifene is taken as a once daily tablet (60 mg/day).
for all fractures. After 3 years of treatment, total hip BMD Side effects include thromboembolic disease (Relative risk was increased by 3.7% in the HRT group compared with similar or lower than that of HRT), flu syndrome, leg Side effects
CALCITONIN
However, the overall results show that health risks It is a polypeptide hormone that exerts its hypocalcemic outweigh these benefits of HRT. Women’s Health Initiative effects directly by inhibiting osteoclast resorption.
study (WHI), and the Million Women study, haveconfirmed that the use of HRT does not reduce the risk of Clinical data
CHD and increases the risk of breast cancer, stroke and Calcitonin, a weak anti catabolic drug, has been shown venous thromboembolic events. As a result of these to increase the lumbar spine BMD in late post menopausal findings, other antiresorptive agents are now the drugs of women by an average of 1-2%. According to the PROOF choice for the prevention and treatment of osteoporosis in study there was a 33% reduction in the risk of new postmenopausal women. Use of HRT is presently limited vertebral fractures in 200 IU calcitonin treated group.
to postmenopausal women with severe hot flushes and Calcitonin has no effect on non vertebral fractures [15].
vaginal and skin changes. HRT should be used for theshortest time possible, at as low a dose as possible in order Treatment of calcitonin should be considered for older to stop the menopausal symptoms (hot flushes) and only women with osteoporosis on multiple medications on those who fail to respond / tolerate other treatments and in acutevertebral fractures because of its analgesic effect.
Dose schedule
Dose schedule
Estrogens are used orally at a dose of 0.3 mg/d for esterified estrogens, 0.625 mg/d for conjugated equine It is currently available as a parenteral and nasal spray estrogens and 5 mcg/d for ethinyl estradiol. For formulation. Administration of salmon calcitonin should transdermal estrogen the recommended dose is 50mcg be as 200 IU daily in alternating nostrils or 100 IU estradiol per day. In women with an intact uterus, progestin parenterally. Nasal calcitonin can produce rhinitis and is added to reduce the risk of uterine cancer.
parenteral calcitonin may cause facial flushing, nausea andvomiting.
SERMS (Selective estrogen receptor modulators)
ANABOLIC DRUGS
This group includes drugs like Tamoxifen and Raloxifene that have tissue- specific effects in classical TERIPARATIDE rhPTH (1-34)
target tissue for estrogen action. Raloxifene like Tamoxifen It is the 1-34 amino acid fragment of the native 84 has antiresorptive effects on bone, but, unlike Tamoxifen, amino acid parathyroid hormone molecule. PTH is an it does not cause endometrial stimulation.
Clinical data
PTH exerts its action on bone through PTH1 receptor.
It can produce both bone resorption and bone formation.
According to the MORE (Multiple Outcomes of Continuous exposure to high dose PTH increases Raloxifene Evaluation) trial, Raloxifene (60 mg/day) after osteoclast differentiation and action leading to bone 3 years of treatment, showed positive effects on bone resorption. In contrast daily injections of low dose PTH mineral density at lumbar spine and femoral neck (2-3% (intermittent exposure) produces increase in osteoblast increase). These increased over time and were independent number and function leading to bone formation.
of dose. The relative risk reduction of new vertebralfractures produced was 30% to 50%. Raloxifene does not, Clinical data
however, have a significant effect on nonvertebral fractures[14].
Randomized controlled trials have demonstrated the efficacy of human parathyroid hormone, (hPTH (1-34), in Apart from the skeletal effects Raloxifene induces a improving bone mass and reducing the risk of fractures in dose dependent decrease of serum total and LDL postmenopausal osteoporosis. In an international fracture cholesterol and may reduce the risk of cardiovascular prevention trial, compared with placebo, teriparatide events especially in women with increased cardiovascular significantly reduced the risk of vertebral fractures by 65-69% and nonvertebral fragility fractures by 53-54% Apollo Medicine, Vol. 3, No. 2, June 2006 Review Article
[16]. In addition to postmenopausal osteoporosis, fractures and 36% for hip fractures in group at high Teriparatide is also a potentially useful therapeutic agent for osteoporosis in men. Orwall, et al. reported increase in Dose schedule
spinal bone mineral density by 5.9% (20 mcg) and 9.0%(40 mcg), femoral neck bone density by 1.5% (20 mcg) Daily oral dose of 2 mg/day. Strontium is well tolerated and 2.9% (40 mcg) and whole body bone mineral content in upper gastrointestinal region. However, it has been by 0.6% (20 mcg) and 0.9% (40 mcg) above baseline after known to be one of the causal agents for osteomalacia in 11 months of teriparatide therapy (once daily).
patients with end stage renal failure on dialysis [22].
Patients are usually considered for Teriparatide Treatment guidelines can be divided into 3 groups [rhPTH(1-34)] treatment either because they remain (i) Asymptomatic patients who need screening for severely osteoporotic or because they have failed antiresorptive therapy. Prior use of antiresorptives hasshown to produce variable effects on PTH action. Ettinger (ii) Patients with definite Osteoporosis.
et al. reported that prior treatment with Raloxifene allows (iii) Patients with fracture due to osteoporosis for the Teriparatide induced BMD increases. In contrast, (i) Asymptomatic patients who need screening
prior treatment with Alendronate prevents increases in for osteoporosis.
BMD, particularly in first 6 months [17]. According to astudy by Cosman et al. PTH when added to HRT, in women All postmenopausal women ( 65 yrs should routinely with osteoporosis, produced significant increase in bone undergo a bone density test to assess baseline status.
mass and density, this elevation persisted for 1 year after discontinuation of PTH while women continued < 65 yrs should be obtained if there is presence of risk Dose schedule
BMD is not recommended routinely in premenopausalwomen, but start prevention with calcium/vitamin D Teriparatide is administered at a dose of 20 mcg/day as if inadequate oral intake/ poor sunlight exposure. One a subcutaneous injection. Because of the occurrence of can consider BMD assessment if multiple risk factors/ osteosarcoma in rats treated with very high doses of teriparatide, the duration of treatment recommended is 18months.
In case of males assess risk factors and secondarycauses. BMD should be done if there is history of STRONTIUM RANELATE
fragility fracture or secondary causes.
It has recently completed phase III clinical trials. It acts (ii) Guidelines for patients with established
by inducing uncoupling in bone remodeling, increases osteoporosis
bone formation by increasing the replication of pre-osteoblasts into oseteoblasts, decreases bone resorption Do complete evaluation with history / physical exam by reducing the differentiation of pre-osteoclasts and routine tests mentioned in medical evaluation into osteoclasts and the bone resorbing activity of above to establish the cause of osteoporosis.
osteoclasts, as a result increasing DXA measured bone Do bone density every year to follow the treatment till Clinical data
Consider bone markers (N-telopeptide and osteo- Strontium Ranelate has shown to produce continuous calcin) if needed to assess early changes during increase in BMD at 3 years by 14.4% at lumbar spine, by follow-up. These are particularly useful in steroid 8.3% at femoral neck and by 9.8% at total hip and bone strength is directly related to bone mineral density. The If metabolic parameters do not indicate significant vertebral antifracture efficacy of Strontium Ranelate was vitamin D deficiency, start treatment with specific demonstrated with reductions in the relative risk of new medication. In general bisphosphonates like vertebral fractures by 49% after one year and by 41% after alendronate / risedronate are the most powerful agents.
three years in postmenopausal women with osteoporosis Risedronate may produce less GI intolerance.
and at least one vertebral fracture receiving daily oral Although unproven in terms of fracture reduction, Strontium (2 g/d) [20]. Non vertebral fracture efficacy in parenteral bisphosphonates like pamidronate and postmenopausal women with osteoporosis is demonstrated zolendronate are also options as they produce by relative risk reduction of 16% for all non vertebral Apollo Medicine, Vol. 3, No. 2, June 2006 Review Article
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