A Treatment Algorithm for Indian Patients of Osteoporosis

Indian Medical Gazette FEBRUARY 2012 67 Symposia Update A Treatment Algorithm for Indian Patients of Osteoporosis Shailendra Mohan Lakhotia, Senior Consultant Orthopedic Surgeon, Kolkata 700 045. Prashant Dongre, Medical Advisor, Novartis India Limited, Worli, Mumbai 400 018. Introduction In an effort to step up the efforts to optimise the comprehensive management of osteoporotic patients in India, the process of collection of the data on current opinion and practices for managing osteoporosis patients began at the 1st Indian Osteoporosis Congress organized in Mumbai, on the 6th of December 2009. A completely interactive electronic vote pad based session was devoted to making a beginning towards a treatment algorithm for Indian patients suffering from Osteoporosis. These issues were presented by Dr. S.M. Lakhotia and fifty (50) delegates from across specialties namely Orthopedics, Rheumatology and Endocrinology participated in the session. The process was anonymous thus enabling the participants to vote without being influenced or inhibited by the choice of others. The elite panel of Dr. Shashank Joshi, Dr. S.M. Lakhotia, Dr. Rohini Handa, Dr. Rajesh Malhotra, Dr. URK Rao and Dr. Erik Erikson (International expert from Norway thoroughly discussed the different aspects emerging out from the opinion of the delegates. This report is generated from the deliberations of 217 specialists involved in managing the patients with osteoporosis, who had responded to an average of 23 questions. Q 1) Do you believe that Osteoporosis is a Problem of the Western population and not seen much in Indian patients? A) Osteoporosis is more of a problem in western population. B) The prevalence could be more in India as osteoporosis occurs earlier in Indian patients. C) Osteoporosis occurs later in Indian population as compared to the Western population D) The severity of osteoporosis is less in Indian patients The success of the session and suggestions led to replication in 11 different venues in the country namely Delhi, Hyderabad, Bangalore, Chennai, Pune, Ahmadabad, Thane, Surat, Chandigarh, Mumbai, Jaipur and Lucknow through vote pad or paper based questionnaire with participation of over 167 specialists from Orthopedics, Rheumatology, Gynecology and Endocrinology to get more robust information on their current approach and opinion so that a consensus can be made towards the development of a treatment algorithm for Indian patients. Address for correspondence: Dr Shailendra Mohan Lakhotia, M.S. (Ortho), Senior Consultant Orthopaedic Surgeon, Krishna Apartment, 160/31/2A, Lake Gardens, Kolkata - 700 045. E-mail: smlakhotia@hotmail.com

68 Indian Medical Gazette FEBRUARY 2012 1. In India exact figures are not available since studies for the prevalence of Osteoporosis is not conducted. Although 87 % of the participants thought that prevalence could be more in Indian patients but in the discussions it was clear that this could be more due to the increased age expectancy. 2. Most delegates agreed that the mean age of Osteoporosis in Indian men and women is similar to that for the western population. 3. They also agreed that Osteoporosis is an underrecognized condition especially in men until the condition is at an advanced stage 1 and apart from old age more than 50 % of the times the cause of male osteoporosis is secondary. all patients in the vulnerable age group, so that with early diagnosis, a requisite treatment can be initiated. Q 3) Should the IOF one minute risk test be utilized to screen all individuals at risk in India? A) Yes it is a very effective tool for mass screening B) No it does not apply to Indians, we will need to validate it for Indian patients C) It is not practical and too long, need to decrease the number of questions D) It is useful only for post menopausal women Q 2) How do you identify patients at risk for osteoporosis? A) BMD measurement by Ultrasound B) All above age 60 with family history and additional risk factors C) History of previous fracture D) All of the above 1. The early identification of an elderly patient at risk of Osteoporosis is critical. 2. This requires enquiring about history of the risk factors including previous fractures and screening 1. The one minute Osteoporosis risk test of the IOF(International Osteoporosis foundation) is a set of 19 questions of which some questions are common and some specific for men and women. This is a validated tool proposed by the International Osteoporosis Foundation to screen and easily identify the patients at risk of osteoporosis. 2. The One minute Osteoporosis risk test of the IOF is a very useful and comprehensive questionnaire and can be used as an early screening method by keeping the copies in the waiting area or administering this with the help of the counselors. 3. It was also suggested that efforts should be made to create an Indian version in local languages and get the Indian version validated by the national and international bodies working in the field of osteoporosis. Q 4) What is the status of measuring BMD by

Indian Medical Gazette FEBRUARY 2012 69 ultrasound in the diagnosis of osteoporosis? A) It does not measure BMD directly. Thus it cannot be used to diagnose osteoporosis B) It is a reliable and cheaper technique to diagnose osteoporosis C) It is a useful tool for mass screening of the population at risk, who need further investigation D) It is useful only in post menopausal women A) Yes, the values apply accurately to Indians as well B) Bone mass appears to be 5-15% lower in Indians than Caucasians, hence a corrective factor needs to be applied. C) They are applicable only to post menopausal women and not to men D) They are not the most accurate but currently the best available standard tool for diagnosis of osteoporosis 1. Ultrasound is at best used for screening and cannot even be used for follow up. Data, apart from post menopausal women are not available. Though the results are not standardized and a lot of variation exists, but as only about 500 DEXA machines are available in the country, this is the next best tool for screening. 2. The advantages for a country like India are that it helps getting the awareness among the people regarding Osteoporosis. It is cheaper and portable, the reports though not very reliable, if appropriately inferred together with the history of risk factors will help in decision for further investigations. Ultrasound could be an important tool especially in rural areas but still only as an educational tool, as a screening tool and not as a diagnostic tool. Q 5) Are the BMD criteria on bone densitometry by DEXA defined by WHO applicable to Indians? 1. Normative BMD data in Indians is lacking and there is a need for data from all parts of the country due to the diversity involved in the different geographies in the country. 2. Some specialists thought that since the bone mass of Indians is 5 to 15% lower than Caucasians, hence a corrective factor needs to be applied. The majority of the specialists felt that though the WHO criteria may not be 100 % accurate for Indian population it is currently the best available standard tool for diagnosis of osteoporosis. Q 6) For a 79 year-old lady, after surgery for a hip fracture, what do you do? A) I order a DXA scan B) I do not need a DXA scan because the diagnosis is obvious C) I refer the patient to another specialist for osteoporosis treatment

70 Indian Medical Gazette FEBRUARY 2012 D) I schedule the patient for a follow up visit and then I will reconsider the case 1. BMD by DEXA should form the basis of diagnosis for osteoporosis as frequently as possible, not only for monitoring but even for the records and litigation. For hip fracture patients, DXA should be done after fracture fixation for records and monitoring the improvement after therapy. 2. At places and situations where DEXA is not available or affordable it must be documented as such along with the reasons for diagnosis of Osteoporosis. Q 8) For the decision of starting drug treatment, what is for you the most important factor? 1. Though most of the orthopedic surgeons felt that DXA scan is not needed for diagnosis in a hip fracture patient, 31% delegates felt that DXA scan should be done at base line to monitor the effect of the treatment. 2. Osteoporotic hip fractures irrespective of T- score should be treated as even the bone quality would be compromised if the osteoporotic condition is not treated. A) DXA scan showing osteoporosis (T-score < -2.5) B) Previous fragility fracture C) Family history of hip fracture D) All, I do not prioritize among these factors Q 7) How often do DXA scans form the basis of your diagnosis for osteoporosis? a) Always b) Frequently c) In selected cases d) Rarely 71% of the specialists felt all the parameters are important. T-score < -2.5 on DXA should be a definite factor for starting drug treatment, but a history of fragility fracture is also an independent factor regarding the initiation of treatment. Q 9) Measurement of BMD with a DXA scan should include minimum which of the sites? a) Lumbar vertebra only b) Lumbar vertebra and femoral neck

Indian Medical Gazette FEBRUARY 2012 71 c) Lumbar vertebra, total hip and wrist d) Lumbar vertebra, femur neck and total hip B) 1 year is practical and acceptable. C) At least 18 months D) 2 years As per the different guidelines, If baseline DEXA is normal and there has been no change in life style then it should be repeated after 3-5 years. 2 If baseline DEXA osteopenic or osteoporotic then repeat after 1 year for 2 years, if BMD is stabilized after 2 years then follow up after every 2 years. 2 1. At least 2 sites BMD should be measured by DEXA: Lumbar vertebra and total hip. 2. Total hip is more reliable and consistent than only the femoral neck. Femoral neck was used earlier when total hip was not available. Total hip/ femur neck becomes especially important in patients >60 years. This is because osteophyte formation at the vertebral bodies and facet joints may interfere with BMD measurement at the spine level. Q 10) When should the DEXA be repeated? A) 8 months If patient is on glucocorticosteroids and being treated for osteopororsis then repeat monitoring after one year may be appropriate. The repeat DEXA scan should be done at the same machine and centre. A point of view expressed by many was that once a year DEXA is important to ensure compliance of patient. If DXA is being done at one year then there is a need to explain to patients that it is done every year to monitor the treatment and not necessarily to see a change and to check that there is no worsening. Q 11) What is the status of bone markers in management of osteoporosis? A) Yes they are useful in diagnosing and evaluating osteoporosis

72 Indian Medical Gazette FEBRUARY 2012 B) Its usefulness is yet not established C) Could be considered for select patients to monitor improvement on therapy D) They should be done routinely for early differentiation of responders from non-responders 1. Bone markers should be done for select patients to monitor the improvement on therapy. 2. Baseline bone turnover markers are weak predictors of the response to therapy with antiresorptive/ anabolic drugs, however, the change in bone markers at 3 months or 6 months compared to the baseline value is of greater value. 3. The results also provide an early positive reinforcement to he patient as well as provides for an opportunity to interact with physician and thus helps to improve compliance with therapy. 3 4. Individual patients can be monitored with bone markers earlier than with DEXA to identify non responders. Utility of bone markers in post hip fracture cases: Though the bone markers will show an increase at the time of hip fracture, this increase will not offset the more than 50 % decrease in resorption markers which is seen after the treatment with bisphosphonates at 3 to 6 months, which is significant and hence bone markers would be a good way to study the effect of the treatment 2. SERMs for the perimenopausal patient may be considered to decrease the menopausal symptoms 3. PTH (Teriparatide) in select and severe cases with multiple vertebral fractures. Q 13) In patients with risk factors and a T score between -1 to -2.5 (Osteopenia) but no fragility fractures you would advise A) Nutritional, lifestyle modifications B) Treatment with calcium and vitamin D C) Treatment with bisphosphonates D) All of the above Q 12) What is your current standard of care for osteoporosis treatment (along with calcium and Vit D)? A) HRT/ SERMS as first line therapy B) Bisphosphonates as first line therapy C) Calcium and Vitamin D only D) PTH (Teriparatide) 1. A bisphosphonate is first line of therapy in almost all the patients of osteoporosis 1. Percentage of osteopenic patients getting fractures is lesser than the percentage of osteoporotic patients

Indian Medical Gazette FEBRUARY 2012 73 getting fractures 4, although numbers in osteopenics look big as that population is larger, hence there is a need to build the calcium and vitamin D stores in these patients. 2. Although treatment may not be warranted for all Osteopenic patients, it should definitely be started to those who have > 2 risk factors. Q 14) Do you routinely do 25 OH Vit D levels to detect Vit D status? A) Never, as all patients have Vit D deficiency and neoplasia/secondary causes of osteoporosis have been ruled out. The patient is still active but limited by the fractures A) I start on oral bisphosphonates (+ Ca and Vit D) B) I start on IV bisphosphonates (+ Ca and Vit D) C) I do not treat the patient because is too old for osteoporosis drugs D) I start with parathyroid treatment B) Only in selected cases of suspected concomitant Osteomalacia C) No, I give Injectable Vit D at beginning of therapy D) Almost for all patients Most of the participants thought that more than 50 % of their patients had concomitant osteomalacia. About 11% participants routinely give injectable vitamin D at the beginning of the therapy. Most prefer to do the 25 OH Vit D levels only in select patients due to the high cost of the test but would prefer to do it more often. It was concluded that 1. 25 OH Vit D levels should be done in as many patients as possible 2. Vitamin D supplementation should be given to bring the serum 25(OH)D level to 30 ng/ml (75 nmol/l) or higher. Q 15) An 82 year-old man has suffered three vertebral fractures, a hip DXA shows a T-score of -3.2 1. Severe Osteoporotic patient: Old, bed ridden and non compliant IV bisphosphonates is preferred. It could be a first choice too for sheer convenience and compliance advantages. Intravenous Zoledronic acid data shows reduction in long term mortality in post hip fracture cases. 2. In severe osteoporosis if patient is relatively younger and compliant with daily dosing - anabolic agent is also a choice 3. Oral bisphosphonates not preferred if patient is very old and activity is limited making it difficult for the patient to follow 4. For pain relief, Calcitonin can be considered along with simple immobilization. Q 16) In patients with risk factors/previous fragility fractures would you prophylactically start antiresorptive therapy with a bisphosphonate to prevent osteoporosis, even if T- scores are not very low?

74 Indian Medical Gazette FEBRUARY 2012 A) Yes definitely in all patients B) No I would not start prophylactically C) Only in patients with glucocorticoid induced osteoporosis D) Only in women with risk factors for postmenopausal osteoporosis and T score >-2 In women with low bone mass who do not meet the bone mineral density criterion for osteoporosis, but if the risk factors and history of previous fragility fractures is present, then bisphosphonates have been shown to be effective in reducing the risk of new (incident) vertebral fractures. Q 17) In a patient of PMO aged 67 yrs with 2 fragility fractures, with T Score for vertebra and hip more than -3 and wrist is -4 (Severe Osteoporosis), you would prefer? A) Oral Bisphosphonates B) Injectable bisphosphonate C) Injection teriparatide S.C. D) Combination therapy (Teriparatide + Zoledronic acid) from the beginning can be considered only in selected high-risk patients, including those with low hip BMD, previous fractures, rheumatoid arthritis, and other serious conditions where a more rapid response is required. 1. For a severe case of osteoporosis, daily subcutaneous injection of teriparatide definitely has a role. 2. After the teriparatide treatment has been stopped after 1.5 to 2 years, it has to be followed by a bisphosphonate to maintain the gains from anabolic treatment or else these gains may be lost due to resorption getting activated. 3. Combination therapy (PTH + ZOL) from the beginning can be considered in very severely osteoporotic patients with high risk for fractures Recent studies with combination treatment (PTH + ZOL) produced increase in BMD faster than either drug alone at both spine and hip 5. Q 18) A patient has been on bisphosphonates for 4 years, with no new fractures during this period A) I keep the patient on treatment up to 10 years B) I stop the drug C) I decide on the basis of BMD. If still within osteoporosis range I continue treatment D) I decide on the basis of biochemical markers and if not too low I continue treatment 1. If T score is <-2.5, the therapy with bisphosphonates should be continued and monitored. Safety data for bisphosphonates use is available for 6 to 10 yrs. 2. Recent evidence shows that atypical

Indian Medical Gazette FEBRUARY 2012 75 critical to switch to bisphosphonates (Oral or IV, depending on convenience) or else the gains from teriparatide are not sustained for long and patients again increase the risk of fractures. Q 20) Do you have patients with issues of compliance to the prescribed therapy? A) Patients have Upper GI Side effects with oral drugs B) Difficult to comply with the instructions for oral bisphosphonates C) Often forget to regularly take the drug subtrochanteric and diaphyseal femur fractures are not related to long term use of bisphosphonates, as their incidence in not significant. 6 3. If BMD is normal continuously for 5 years then the bisphosphonate therapy can be stopped, though there is a chance that risk of fracture may increase after stopping bisphosphonates. Q 19) In a patient who had therapy with teriparatide for one and half years, do you believe that he needs to be switched over to antiresorptive treatment to maintain the gain in BMD? Which one do you choose? A) Yes, switch to oral bisphosphonates B) Yes, switch to IV bisphosphonates C) Yes, switch to SERMS (Raloxifene ) D) No, he needs to be continued on Calcium and Vit D only After completing therapy with teriparatide, (PTH) it is D) No issues with the oral therapy Comparative data showing the difference in relative fracture protection if patients miss their weekly or monthly dose of osteoporosis medication or if they miss half their doses of medication 8. Relative Fracture Protection (%) 100 90 80 70 60 50 40 30 20 10 0 100 % No Doses Missed 64% less protection 94% less protection 36 % One Dose Missed Weekly/Month 6 % Half of Doses Missed Adapted from Siris E. S. et al. Mayo Clin Proc. 81(8):1013-1022, 2006. Data shows that within 1 year of initiating treatment for osteoporosis, 45% of patients do not continue the oral

76 Indian Medical Gazette FEBRUARY 2012 drugs. Siris et al. found that at 24 months, 80% were non persistent with oral bisphosphonate therapy 7. 1. Regarding the reasons for non-compliance with oral bisphosphonates, there was an overlap in most patients; many patients forget to take the drug regularly, while the lack of compliance in some patients is due to difficulty in following the instructions for oral bisphosphonates, but 29 % delegates felt that their patients have upper GI side effects that prevent the compliance to therapy. There is also a high amount of subjectivity among these issues depending on social strata of patient. 2. Counselling and interactive session amongst the patients and regular checkups and BMD monitoring would be helpful to overcome the real world challenges of compliance. More than 85% specialists also felt that providing an option of once yearly dosing would also ensure compliance in patients having problems with oral therapy. Q 21) Do you believe that women with osteoporosis who are currently taking estrogen should discontinue it immediately due to the risks shown in the Women s Health Initiative study, and switch to a bisphosphonate for prevention or treatment of osteoporosis? A) Yes definitely B) No not necessarily, can be continued for perimenopausal women for relief of menopausal symptoms C) In women with family history of breast cancer D) In women with risk factors for a stroke The risks shown in the Women s Health Initiative study are significant when estrogens are used for a long period 8, but estrogens can still be used in certain peri-menopausal osteoporosis cases to tide over the menopausal symptoms and then shift to a bisphosphonate in due course. Q 22) In your clinical practice, before starting Injectable Bisphosphonate do you routinely do the creatinine levels and calculate creatinine clearance? A) Yes B) Not required C) Only for patients with renal disease D) Only for very old patients 73 % of the specialists routinely do the creatinine levels and calculate creatinine clearance before starting an IV bisphosphonate, whereas 17% do it only for patients with history of diabetes or renal disease and 5 % do it if the patients are very old. It was concluded from the deliberations that 1. Creatinine levels and creatinine clearance should be calculated before starting an IV bisphosphonate 2. Creatinine clearance should be above 35 ml/min, before starting any IV bisphosphonate Q 23) In a patient with Hip fracture, should Zoledronic acid be administered to prevent the recurrence of fracture?

Indian Medical Gazette FEBRUARY 2012 77 A) Yes, after 2 weeks B) Not required C) No, Start with oral Bisphosphonates D) No, start with teriparatide 1. Patients of osteoporotic hip fractures need to be treated for the underlying osteoporosis with bisphosphonate therapy. 2. Zoledronic acid is the only bisphosphonate which has data to prove that it prevents the recurrence of any new fractures ( including recurrent hip fracture) in post hip fracture patients 9. 3. Zoledronic acid is the only bisphosphonate which also significantly decreases the long term mortality due to hip fractures 9. 4. Zoledronic Acid does not prevent bone healing. These advantages make zoledronic acid the preferred therapy for post hip fracture patients according to the panel and delegates. The data shows that the significant results are seen when the infusion is done 2 weeks after the hip fracture fixation. Many of the delegates shared their experience of having infused some of their hip fracture patients with zoledronic acid 3 to 4 days post operatively or one day before discharge with monitoring for 24 48 hours for any infusion related side effects. The NSAIDS were also started simultaneously and continued for 4-5 days after discharge. Conclusion The data discussed above provides a direction towards developing a treatment algorithm for Indian patients suffering from osteoporosis, this provides practical tool to health care professionals who are involved in osteoporosis management. The areas that require urgent attention are research to establish hip fracture incidence in India, further education of the health care professionals, awareness among general population regarding osteoporosis and development of guidelines by a national body for diagnosis and treatment of Indian osteoporotic patients. Acknowledgement We wish to thank all the participants, who helped in developing the consensus during the different meetings held across the country for obtaining the insights into the current opinion of the specialists involved in the management of osteoporotic patients Presented as an oral paper presentation by Dr. S.M. Lakhotia in the 2nd Indian Osteoporosis Congress held by the ISBMR (Indian Society of Bone and Mineral Research) on 10th October 2010 in Mumbai. References 1. Sawka A.M. J Rheumatol. 31(10):1993, Oct 2004. 2. AACE Medical Guidelines for Clinical Practice for the Prevention and of Postmenopausal Osteoporosis: 2001 Edition, With Selected updates for 2003, Endocr Pract. 2003; 9 (No. 6). 3. Delmas P.D. et.al. Jour Clin Endo and Metab. 92(4):1296, 2007. 4. Siris E.S. et al. Bone Mineral Density Thresholds for Pharmacological Intervention to Prevent Fractures. Arch Intern Med. 164:1108-1112, 2004. 5. Cosman F., Eriksen E.F. et al. Effects of intravenous zoledronic acid plus subcutaneous teriparatide [(1-34)rhPTH] in postmenopausal osteoporosis. J Bone Miner Res. [Epub ahead of print] Sep 2, 2010. 6. Black D.M. Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med. 362(19):1761-1771, May 13, 2010. 7. Siris E.S., Harris S.T. et al. Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases. Mayo Clin Proc. 81(8):1013-1022, 2006. 8. Anderson G.L., Limacher M., Assaf A.R., et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women s Health Initiative randomized controlled trial. JAMA, 291 (14): 1701 1712, 2004. 9. Lyles K.W., Colon-Emeric C.S. et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 357(18):1799-1809, 2007.