Management of Vitamin D Deficiency and Osteoporosis in Clinical Practice

1. Management of Vitamin D Deficiency and Osteoporosis in Clinical Practice M. Ali Karamat MBBS MRCP MD FRCP Consultant Physician and Honorary Senior Lecturer

2. ­ PTH ­Ca2+ reabsorption & ­1,25 DHD bone resorption ­ Ca2+ availability ­ Ca2+ absorption Overview of calcium homeostasis ¯ Ca2+

3. Vitamin D metabolism1,2 Metabolism of vitamin D • National Osteoporosis Society Practical Guidelines. Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management. April 2013. Available at: http://www.nos.org.uk/document.doc?id=1352 • Adapted from Fraser WD and Milan AM. Calcified Tissue Intl 2013; 92(2): 118-127.

4. Vitamin D is a multifunctional prohormone1 Renal and extrarenal 1,25(OH)2D3 production serves endocrine, autocrine and paracrine functions • Adapted from Dusso AS et al. Am J Physiol Renal Physiol 2005; 298(1): F8-28.

5. Manifestations and symptoms of vitamin D deficiency1 • National Osteoporosis Society Practical Guidelines. Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management. April 2013. Available at: http://www.nos.org.uk/document.doc?id=1352

6. Relationships between vitamin D and musculoskeletal health…….. Calcium absorption, bone mineral density (BMD) and osteomalacia1 Parathyroid hormone (PTH)2,3 • Adapted from IOM (Institute of Medicine). Dietary reference intakes for calcium and vitamin D. Washington; DTNAP; 2011. • Adapted from Krall EA et al. N Engl J Med 1998; 321(26): 1777-83. • Adapted from Arabi A et al. Bone 2010; 47(2): 408-12.

7. Relationships between vitamin D and… Fractures1 Cardiovascular risk2 • Adapted. from Bischoff-Ferrari HA et al. NEJM 2012; 367(1): 40-49 • Adapted from Wang L et al. Circ Cardiovasc Qual Outcomes 2012; 5: 819-29.

8. Persistently low Vitamin D status predisposes >75 year old women to fractures Swedish population based prospective study on BMD, falls, fractures N = 987, final report available for 640 women (>75 years old) Osteoporosis Int. 2014;25(Suppl 2). Abstract OC19

9. Relationship between vitamin D and length of hospital stay in the elderly1 • Vitamin D insufficiency (≤50nmol/L) was associated with a 3-day longer hospital stay in elderly inpatients (15.2±8.2 vs. 12.1±7.0 days, p=0.017) • 25OHD concentration inversely correlated (r=-0.14, p=0.028) and was inversely associated with length of stay (adjusted β=-0.07, 95% CI -0.14 to -0.02, p=0.043) • Adapted from Hélard L et al. Dis Markers 2013; 35(5): 525-9.

10. During the winter months there is inadequate sunlight in the UK to synthesise vitamin D1 Vitamin D insufficiency is common in the UK population2 There is a significant north-south gradient in the prevalence of vitamin D insufficiency/deficiency1 Up to 50% of adult population in the UK will be vitamin D insufficient in winter and spring, with 16% having severe deficiency2 In summer and autumn, 28% of adult population in Scotland will be vitamin D insufficient, with 8% having severe deficiency1 • Hyppönen E and Power C. Am J Clin Nutr 2007; 85(3): 860-8. • Pearce SHS and Cheetham TD. BMJ 2010 Jan 11; 340: b5664. doi:10.1136/bmj.b5664.

11. The Chief Medical Officers defined at risk groups of vitamin D deficiency in clinical practice in February 20122 • National Osteoporosis Society Practical Guidelines. Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management. April 2013. Available at: http://www.nos.org.uk/document.doc?id=1352 • https://www.gov.uk/government/publications/vitamin-d-advice-on-supplements-for-at-risk-groups • http://www.nice.org.uk/nicemedia/live/13795/67630/67630.pdf

12. Recommended thresholds for treatment However, reliable routine serum 25OHD measurement tests may not be accurate below 30nmol/L. Evidence suggests tests have a limit of quantification ranging from 10–22.5nmol/L2-4 • National Osteoporosis Society Practical Guidelines. Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management. April 2013. Available at: http://www.nos.org.uk/document.doc?id=1352 • Turpeinen U et al.Clin Chem 2003; 49(9): 1521-24. • Janssen MJW et al. Clin Lab 2014; 60: Available at: http://www.clin-lab-publications.com/files/eaop/2014_01+02/130223-Janssen.pdf • Knudsen CS et al. Clin Chem Lab Med 2012; 50(11): 1965-8. *Reference levels may differ in this range.

13. Recommended dosing strategy *In primary care, where rapid correction may often not be required, maintenance therapy may be started without the use of loading doses EFSA advises an upper limit of 4000 IU/day is safe for adults and children >11 years of age1 * European Food Safety Authority • EFSA Panel on Dietetic Products NaAN. Scientific opinion on the tolerable upper intake level of vitamin D. EFSA Journal 2012; 10(7): 2813. • National Osteoporosis Society Practical Guidelines. Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management. April 2013. Available at: http://www.nos.org.uk/document.doc?id=1352

14. 3200 IU/day is sufficient for restoring daily vitamin D concentrations no need for 20KIU when rapid repletion is not required • Dose response to vitamin D3 treatment in healthy postmenopausal women was curvilinear and tended to plateau at approx. 112 nmol/L in patients receiving more than 3200 IU/day1 • Gallagher JC et al. Ann Intern Med 2012; 156: 425-37.

15. Pregnancy & Lactation CMOs’ letter February 2012* - The following groups of people are at risk of vitamin D deficiency: • All pregnant and breastfeeding women, especially teenagers and young women. Recommendations All UK Health Departments recommend: • All pregnant and breastfeeding women should take a daily supplement containing 10μg of vitamin D, to ensure the mother’s requirements for vitamin D are met and to build adequate foetal stores for early infancy. *specific to pregnancy and lactation

16. NICE November 2014 Vitamin D: increasing supplement use among at-risk groups NICE public health guidance 56 11 key recommendations • Recommendation 1 Increase access to vitamin D supplements • Recommendation 2 Clarify existing guidance • Recommendation 3 Develop national activities to increase awareness about vitamin D • Recommendation 4 Ensure a consistent multiagency approach • Recommendation 5 Increase local availability of vitamin D supplements for at-risk groups • Recommendation 6 Improve access to Healthy Start supplements • Recommendation 7 Only test vitamin D status if someone has symptoms of deficiency or is at very • high risk • Recommendation 8 Ensure health professionals recommend vitamin D supplements • Recommendation 9 Raise awareness among health, social care and other relevant practitioners of • the importance of vitamin D • Recommendation 10 Raise awareness of the importance of vitamin D supplements among the local • population • Recommendation 11 Monitor and evaluate the provision and uptake of vitamin D supplements

17. Treatment of choice in vitamin D deficiency1 Vitamin D3 vs. calcium/vitamin D3 combination • Not all patients need the added calcium the combination provides • Guidelines state calcium/vitamin D3 should not be used as sources of vitamin D, given the high doses of calcium required if treating deficiency in combination1,2 Unlicensed • The Advice from the Royal Pharmaceutical Society, the National Pharmacy Association and the MHRA is that wherever possible, a licensed medicine should be supplied against a prescription3 • Recent publications have shown unlicensed preparations can have significant variances between actual content and label strength. One analysis showed variances in label claim versus actual from 8+ 2% to 210+ 29%4. • National Osteoporosis Society Practical Guidelines. Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management. April 2013. Available at: http://www.nos.org.uk/document.doc?id=1352 • Data on file Internis Pharmaceuticals Ltd D2. • http://www.gmc-uk.org/guidance/ethical_guidance.asp. Accessed October 2014 4. http://www.ncbi.nlm.nih.gov/pubmed/23364495 . *NOS – National Osteoporosis Society

18. Challenges with unlicensed unregulated supplements • Variable content • 14.3–171% of label content leading to poor control1 • 8–201% of label content2 • 3 cases of hypervitaminosis D, hypercalcaemia and renal insufficiency in patients taking oral vitamin D supplement3 • Declared vitamin D3 content 600 IU per capsule vs. actual content approx. 880 times higher3 • No medical information or pharmacovigilance • No yellow card adverse event reporting • Unregulated excipients • No TSE certification Evidence suggests vitamin D intoxication due to use of unlicensed supplements is not rare.3 Vitamin D supplements do not undergo quality control and may be dangerous to consumers’ health. Given preparations labeled ‘food’ are commonly used without medical prescription, their contents should be strictly regulated3 Data on file. Internis Pharmaceuticals Ltd. Garg S et al. J Nutr Health Aging 2013; 17(2): 158-61. Benemel S et al. Brit J Clin Pharmacol 2013; 76(5): 825-6. *TSE – transmissible spongiform encephalopathy

19. Safety of vitamin D treatment in the licensed form • Vitamin D is well known and has been widely used in clinical practice for many years1 • Toxicity is most likely to occur in chronic overdosage where hypercalcaemia could result2 • Doses above 10,000 IU/day are associated with toxicity2 • Doses ≥50,000 IU/day for several weeks or months are frequently associated with toxicity, including documented hypercalcaemia2 • Data on file. Internis Pharmaceuticals Ltd. • IOM (Institute of Medicine). Dietary reference intakes for calcium and vitamin D. Washington; DTNAP; 2011. • Adapted from Vieth R. Ann Epidemiol 2009; 19(7): 441-5. • EFSA Panel on Dietetic Products NaAN. Scientific opinion on the tolerable upper intake level of vitamin D. EFSA Journal 2012; 10(7): 2813.

20. Queen Mary University 23-25th April 2014 • 2.129. Incidences of High to Toxic 25-Hydroxy Vitamin D Levels amongst Users of a Direct-to-the-Public Blood Spot Vitamin D Testing Service Direct to Public Blood Spot Testing Service DBS • Shea & Berg • 69 users (1.5%) had 25OHD >220 nmol/l • Only 2 under medical supervision • 6 patients had 25OHD >500 nmol/l and were taking 11,000-100k IU/day • Yet, 55% of users with 25OHD >220 nmol/l were taking 10KIU/day or less • Conclusion: Highlights the fact that it is vital that public awareness is increased on the risks of self-administration and over-treatment. • Asks: How many people are over supplementing unknowingly as • they have not had their levels checked?

21. Vitamin D2 & metabolised vitamin D treatments Vitamin D2 • Vitamin D2 as a lower tissue bioavailability especially after intermittent bolus dosing1 • Vitamin D3 is the NOS recommended treatment of choice1 Metabolised Vitamin D treatment such as Alfacalcidol, one alpha and Calcitriol • Restricted for use only in renal impairment2 • Additional twice weekly serum calcium levels monitoring required • Variable cost depending on dose response, other costs are calcium testing and HCP time as weekly testing is required 1.http://www.nos.org.uk/page.aspx?pid=183&srcid=325- accessed Oct 2013 2. https://www.medicines.org.uk/emc/medicine/2449

22. Signs & symptoms associated with Hypercalcaemia • Polyuria/polydipsia • Constipation • Gastric ulcer disease • Muscle weakness • Renal stones • Bone pain

23. Causes of hypercalcaemia • Common • Malignancy (metastatic via cytokines & humoral via PTH-rp) • Primary and secondary hyperparathyroidism • Rare • Hyperthyroidism • Thiazide diuretics

24. Treatment of severe symptomatic hypercalcaemia • Almost inevitably occurs in malignancy • • Volume expansion • Saline (care with CCF/RF) • Furosemide • • Administer iv bisphosphonate (pamidronate) • In very rare and severe cases of hypercalcaemia • (Ca2+ 4.5 – 5 mmol/L), haemodialysis may be used

25. Overview of approved osteoporosis treatments in the UK1-3 IV, intravenous. All product SmPCs can be found at https://www.google.co.uk/?gfe_rd=cr&ei=jPzGVqnHEuPW8geKvq-IAg&gws_rd=ssl#q=emc Trademarks registered to companies as stated on trademark registry

26. Overview of approved osteoporosis treatments in the UK1-3 mAb, monoclonal antibody; PTH, parathyroid hormone; rh, recombinant human; SERM, selective estrogen receptor modulator. All product SmPCs can be found at https://www.google.co.uk/?gfe_rd=cr&ei=jPzGVqnHEuPW8geKvq-IAg&gws_rd=ssl#q=emc Trademarks registered to companies as stated on trademark registry • National Osteoporosis Society website. Drug treatments for osteoporosis. Available at: https://www.nos.org.uk/scans-tests-drugs/drug-treatments. • ConbrizaSmPC. Pfizer Ltd. 17/04/2014. • MiacalcicSmPC. Novartis Pharmaceuticals UK Ltd. 09/12/2015.

27. Anti-fracture efficacy of approved treatments for postmenopausal women with osteoporosis*1 • *When given with calcium and vitamin D. A=Recommendation based on meta-analysis of randomised controlled trials (RCT) or at least one RCT, nae, not adequately evaluated; rhPTH, recombinant human parathyroid hormone; # in subsets of patients only (post-hoc analysis). • National Osteoporosis Guideline Group. Osteoporosis: Clinical Guideline for Prevention and Treatment. July 2010. Available at: https://www.shef.ac.uk/NOGG/NOGG_Executive_Summary.pdf.

28. Bisphosphonates have been shown to prevent both vertebral and non-vertebral fractures1 • Meta-analysis for alendronate relative to placebo resulted in a: • RR of vertebral fracture of 0.56 (95% CI 0.46–0.68, 4RCTs, n=7,039) • RR of hip fracture of 0.62 (95% CI 0.40–0.98, 3 RCTs, n=7,455) • RR of wrist fracture of 0.67 (95% CI 0.34–1.31, 4 RCTs, n=7,931) • RR for other non-vertebral fractures of 0.81 (95% CI 0.68–0.97, 6 RCTs, n=9,973) • Meta-analysis for etidronate relative to placebo resulted in a: • RR of vertebral fracture of 0.40 (95% CI 0.20–0.83, 3 RCTs, n=341) • RR of hip fracture of 0.50 (95% CI 0.05–5.34, 2 RCTs, n=180) • RR for other non-vertebral fractures of 1.04 (95% CI 0.64–1.69; 4 RCTs, n=410) • There were no data for wrist fracture • Meta-analysis for risedronate relative to placebo resulted in a: • RR of vertebral fracture of 0.61 (95% CI 0.50–0.75, 3 RCTs, n=2301) • RR of hip fracture of 0.74 (95% CI 0.59–0.93, 3 RCTs, n=11,770) • RR of wrist fracture of 0.68 (95% CI 0.43–1.08, 2 RCTs, n=2439) • RR for other non-vertebral fractures of 0.76 (95% CI 0.64–0.91, 5 RCTs, n=12,399) • NICE technology appraisal guidance TA160. October 2008. Available at: https://www.nice.org.uk/guidance/ta160.

29. Bisphosphonates are considered first line treatment for the primary prevention of osteoporotic fragility fractures1 Postmenopausal women Initial treatment offered is alendronate Alternative treatment option 1 –risedronateor etidronate when women: Alternative treatment option 2 –strontium ranelate when women: • are unable to comply with administration of, or have a contraindication to or are intolerant of alendronate and • have a combination of T-score, age and number of clinical risk factors. • are unable to comply with administration of, or have a contraindication to or are intolerant of alendronate and either risedronate or etidronateand • have a combination of T-score, age and number of clinical risk factors. • NICE technology appraisal guidance TA160. October 2008. Available at: https://www.nice.org.uk/guidance/ta160.

30. Bisphosphonates are considered first line treatment for secondary prevention of osteoporotic fragility fractures1 Postmenopausal women Initial treatment offered is alendronate Alternative treatment option 1 –risedronateor etidronatewhen women: Alternative treatment option 3 – teriparatidewhen women: Alternative treatment option 2 – strontium ranelatewhen women: • are unable to comply with administration of, or have a contraindication to or are intolerantof alendronate and • have a combination ofT-score, age and number of clinical risk factors. • are unable to take, have a contraindication to or are intolerant of alendronate and either risedronate or etidronate, or • have a contraindication to, or are intolerant of strontium ranelateor • have had an unsatisfactory response to treatment with alendronate, risedronate or etidronateand • have a combination of T-score, age and number of fractures. • are unable to comply with administration of, or have a contraindication to or are intolerant of alendronate and either risedronate or etidronateand • have a combination of T-score, age and number of clinical risk factors. • NICE technology appraisal guidance TA161. October 2008. Available at: https://www.nice.org.uk/guidance/ta161.

31. Bisphosphonate therapy is associated with poor adherence in the treatment of osteoporosis1 • Both compliance and persistence are suboptimal for postmenopausal women undergoing bisphosphonate therapy for the treatment of osteoporosis • 80% of patients are non-compliant within one year of bisphosphonate treatment initiation2 Adherence + Compliance Persistence The length of time from beginning to completion or discontinuation of therapy The consistency and accuracy with which a prescribed regimen is followed Few strategies attempting to improve adherence have demonstratedclinical outcomes – the design and development of new programmesor treatments to improve adherence to these drugs is needed • Imaz I et al. Osteoporosis Int 2010; 21: 1943–1951. • Data on File. Internis Pharmaceuticals Ltd. D1

32. At least one third of new bisphosphonate patients treated with tablets will not receive a further prescription1 • Data on file. Internis Pharmaceuticals. 2015.

33. GI side effects are the main reason for stopping oral bisphosphonate therapy1 • Difficulty or discomfort in swallowing (dysphagia) is common, especially among elderly people, and the perceived potential for upper GI problems is a barrier to good long-term adherence • In a normal clinical setting, GI adverse events are among the most common reasons for giving up oral bisphosphonate therapy • Generic bisphosphonate formulations have been shown to be associated with an increase in upper GI adverse events, leading to therapy discontinuation Multiple factors contribute to the developmentof clinical GI effects and should be considered: • Lack of education on expected side effects • Gastric acid conditions • Length ofcontactof the tablet Reflux • The chemical formula of the molecule • Brandi M and Black D. Clin Cases Miner Bone Metab 2013; 120(3): 187–190.

34. Managing GI tolerability could be the key for your patients who discontinue alendronate therapy1,2 • GI side effects are the most common reason for alendronate discontinuation2 • Alendronate tablets can contribute to gastric irritability in a number of ways2,3 Oesophageal ulcers Oesophagitis Dysphagia Dyspepsia • Early tablet dissolution • Slow transit time Hazardous reflux Less acidic • Acid reflux More acidic • Brandi M and Black D. Clin Cases Miner Bone Metab 2013; 120(3): 187–190. • Invernizzi M et al. Aging Clin Exp Res 2015; 27: 107–113. • AccotoCG et al.Calcif Tissue Int 2012; 91: 325–334.