Endocrinology of Bone PDF

Disorders of Bone and Calcium Metabolism 10-23-2023 Alan Malabanan, MD, CCD Director, Bone Health Clinic Director, Endocrine Clinic Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Financial Disclosure None Objectives...

Disorders of Bone and Calcium Metabolism 10-23-2023 Alan Malabanan, MD, CCD Director, Bone Health Clinic Director, Endocrine Clinic Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Financial Disclosure None Objectives • Describe the process of bone turnover and its disruption in metabolic bone diseases • Identify factors necessary for normal bone mineralization and bone strength • Review the regulation of calcium and phosphate homeostasis • Recognize the clinical manifestations of metabolic bone diseases • List the oral effects of medications used in the prevention and treatment of osteoporosis Overview The structure and function of bone The basics of bone biology Bone turnover: resorption, formation and mineralization Calcium, phosphate, alkaline phosphatase and Type I collagen Manifestations of altered bone biology Osteoporosis Hyper- and hypoparathyroidism Osteomalacia Important Abbreviations Used  PTH-parathyroid hormone  RANK(L) – Receptor Activator of Nuclear Factor κ B (ligand)  OPG-osteoprotegerin  M-CSF- macrophage colony stimulating factor  TNAP-tissue non-specific alkaline phosphatase  PPi-inorganic pyrophosphate  Pi-inorganic phosphate  ECF-extracellular fluid  VDR-vitamin D receptor  FGF23-fibroblast growth factor 23  ONJ-osteonecrosis of the jaw  AFF-atypical femoral fracture  FRAX-Fracture Risk Assessment Tool  APR-acute phase reaction  CVD-cardiovascular disease  DVT-deep venous thrombosis  CVA-cerebrovascular accident Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Function of Bone Protection of vital organs Locomotion Blood formation Calcium and phosphate homeostasis Structure of Bone Organic matrix: Type I collagen and non-collagenous proteins COL1A and COL1B, Amino acids, vitamin C Hydroxyapatite: calcium and phosphate Vitamin D, calcium, phosphate, magnesium, zinc Bone Remodeling Allows release of calcium, phosphate and magnesium into the circulation Allows removal of damaged or old bone and repair Disruption leads to bone loss, excessive bone growth, weaker bone, and adynamic bone Bone Remodeling Cycle Origination Activation Resorption Formation Mineralization Courtesy of Dr. Susan Ott from http://courses.washington.edu/bonephys/Gallery/Flashmovies/opmovies.html Regulation of Bone Resorption From: Teitelbaum., Science 289:1504, 2000. Regulation of Bone Formation SCLEROSTIN From RT Moon et al. Science 296:16444, 2002. Regulation of Bone Mineralization Requirements 1.Calcium 2.Phosphate 3.Alkaline Phosphatase From Millan et al. Calcif Tissue Int (2016) 98:398–416 Alkaline phosphatase requires Mg and Zn for function. NaPi2b expression NaPi2a retrieval Smit et al. Endocrine Reviews 40: 1468 – 1480, 2019 Calcium and Phosphate Homeostasis Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Calcium Sensing Receptor (CaSR) is the “Thermostat” • Ligands • Ca+2 Mg+2 Aromatic amino acids Ligand binding suppresses PTH release From Primer 5th Edition PTH Response to iCa Change Brent et al. J Clin Endocrinol Metab 67, 944–950 (1988). 17 Vitamin D is a Hormone Necessary for Calcium and Phosphate Homeostasis. 7-dehydrocholesterol PRE-VITAMIN D DIET, SUPPL VITAMIN D LIVER 25-HYDROXYVITAMIN D (25OHD) (-) ↑ GI absorption CA, P PTH WHAT WE MEASURE KIDNEY 1,25-DIHYDROXYVITAMIN D (1,25OHD) ACTIVE HORMONE From Primer 5th Edition Vitamin D Sources • Sunlight (UV-B) 3000 IU per 0.5 MED • Supplements – 400-1000 IU per multivitamin • Food – Fortified milk, OJ, cereal, yogurt: 100 IU/8 oz – Fatty fish: 100-1000 IU/3.5 oz – Fresh shiitake mushrooms 100 IU/3.5 oz – Sun-dried shiitake mushrooms 1600 IU/3.5 oz Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine From: Holick M. N Engl J Med 2007;357:266-281 Causes of Vitamin D Deficiency • Decreased skin production. – Aging, melanin, sunblock – Season, latitude, time of day • Decreased bioavailability: Obesity, malabsorption • Increased catabolism. – Anticonvulsants, steroids, Anti-retrovirals, immunosuppression • Decreased production of 25(OH)D (liver disease) • Decreased production of 1,25(OH)D (kidney disease) Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Holick M. N Engl J Med 2007;357:266-281 Endocrine Society Guidelines (2011) 25OHD Levels ng/ml nmol/L < 20 < 50 21-29 50-74 ≥ 30 ≥ 75 > 100 > 250 Health Status Vitamin D Deficiency Vitamin D Insufficiency Vitamin D Sufficiency Vitamin D Toxicity Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine From Primer 5th Edition Calcium & Vitamin D RDA 2011 AGE CALCIUM VITAMIN D 19-30 y 31-50 y 1000 mg 1000 mg 600 IU* 600 IU* 51-70 y 1000 mg M 1200 mg F 600 IU* > 70 y 1200 mg 800 IU* * 1500-2000 IU may be required to maintain 25OHD levels > 30 ng/ml Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine How much calcium is 1000 mg? ~ 3 cups of milk ~ 5 oz of cheese ~ 10 cups of broccoli ~ 3 tablets of calcium citrate regular size 5 tablets of calcium citrate petite size 2500 mg of calcium carbonate (~3 Tums EX or 2 Oscal) Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine What Lowers Serum Calcium? Decreased calcium absorption Increased calcium excretion Low dietary calcium Vitamin D deficiency Chronic Kidney Disease Aging, Achlorhydria Glucocorticoids Malabsorption Sodium Protons (High animal protein diet) High coffee intake Loop diuretics Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Part I Summary  Bone Turnover plays an important role in calcium homeostasis as well as bone repair and renewal  Bone mineralization requires adequate calcium, phosphate and an active alkaline phosphatase.  Calcium and phosphate homeostasis requires an interplay of PTH, vitamin D, and FGF23 and involves bone, kidney and GI tract  Optimizing calcium and phosphate levels (i.e. bone mineralization) involves adequate calcium and vitamin D intake.  Other nutrients, such as vitamin C, magnesium and zinc are important in maintaining good bone health Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Questions? Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Metabolic Bone Diseases Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Why does it matter? Oral manifestations may be first sign of metabolic bone disease Metabolic bone disease may affect dental development Metabolic bone disease may affect dental health Metabolic bone disease may affect dental treatment outcomes Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Osteoporosis Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Case 65 yo woman presents for a new patient visit. Regular dental care until 2 years ago. Diagnosed with osteoporosis recently. Thoughts? Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Osteoporotic Fracture is Common • 12.3 million Americans have osteoporosis and > 40 million having low bone density • 2 million new osteoporotic fractures annually increasing to 3.2 million by 2040 • 80-95% of hip fracture patients discharged with no antifracture treatment or management plan 2022 Bone Health and Osteoporosis Foundation Clinician’s Guide What is Osteoporosis? Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Fragility fracture in absence of other metabolic bone disease Bone density (BMD) T-score ≤ -2.5 lumbar spine, femoral neck, total hip, or 1/3 radius, even in absence of prevalent fracture T-score between −1.0 and −2.5 and a fragility fracture of proximal humerus, pelvis, or distal forearm Osteopenic BMD with FRAX score 10 y major osteoporotic fracture risk ≥ 20% or hip fracture risk ≥ 3% NIH Consensus 2000; AACE 2020 Update Guidelines in Camacho et al. Endo Pract 2020 By Anatomy & Physiology, Connexions https://commons.wikimedia.org Osteoporosis Risk Factors  Age  Gender  Weight  Height  Previous fracture  Parental hip fracture  Current smoking  Glucocorticoids  Alcohol use (≥ 3 units/d)  Secondary osteoporosis  Type 1 Diabetes Mellitus  Osteogenesis Imperfecta  Hyperthyroidism  Hypogonadism  Menopause < 45 y  Chronic malnutrition  Malabsorption  Chronic Liver Disease  Rheumatoid arthritis From: http://www.shef.ac.uk/FRAX/tool.aspx Green, A. D. Does This Woman Have Osteoporosis? JAMA 292, 2890 (2004). From http://www.dentalcare.com Which one has osteoporosis? Osteoporosis and Oral Health Mandibular bone loss parallels bone loss at extra-oral sites. Panoramic mandibular index (PMI). Mental index (MI). Klemetti index. Anterior maxilla - trabecular bone TMJ dysfunction? Periodontal disease? Dervis et al, 2005; Jeffcoat et al, 2005. Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine From MK Jeffcoat et al, Periodontology 2000; 23:94-102, 2000. From Geurs NC et al. Periodontology 2000, 32:105–110, 2003. Osteoporosis Treatments MEDICATION ROUTE VFX EFFICACY NVFX EFFICACY COST SIDE EFFECTS ALENDRONATE PO ++++ ++++ $ GI, Ca, AFF, ONJ RISEDRONATE PO ++++ ++++ $$ GI, Ca, AFF, ONJ IBANDRONATE PO, IV ++++ + $$ GI (po), Ca, AFF, ONJ ZOLEDRONATE IV +++++ ++++ $$$ Ca, APR, ONJ, AFF DENOSUMAB SQ +++++ ++++ $$$$ Ca, ONJ, AFF, cellulitis RALOXIFENE PO +++ $$ Hot flashes, DVT, CVA CALCITONIN nasal +++ $$ Rhinorrhea, Cancer TERIPARATIDE SQ +++++ ++ $$$$$ Ca , osteosarcoma ABALOPARATIDE SQ +++++ ++++ $$$$$ Ca , osteosarcoma ROMOSOZUMAB SQ +++++ +++ $$$$$ Ca, ONJ, AFF, CVD Data from Camacho et al, Endo Pract 2016 and The Medical Letter 9/29/2014 PO: orally IV: intravenously SQ: subcutaneously Osteoporosis Treatments  Antiresorptives  Bisphosphonates – long-acting pyrophosphate analogs which bind tightly to bone and potently inhibit osteoclast function and bone resorption, ONJ  Estrogen/Selective estrogen receptor modulators – bind to estrogen receptors and modestly inhibit osteoclast function and bone resorption, no ONJ  Denosumab – monoclonal antibody binding to RANK-L and potently inhibits bone resorption, ONJ  Calcitonin – mild inhibitor of osteoclast function, no ONJ  Anabolics  Teriparatide/Abaloparatide – bind to PTH receptors for short-term stimulating osteoblast function, no ONJ  Romosozumab-monoclonal antibody binding to sclerostin, partial antiresorptive and partial anabolic agent, ONJ Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine What is osteonecrosis of the jaw? • Current or previous treatment with antiresorptive or antiangiogenic agents • Exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region > 8 weeks • No history of radiation therapy or obvious metastatic disease to the jaws • Diff dx: alveolar osteitis, sinusitis, gingivitis/periodontitis, caries, periapical pathology, fibro-osseous lesion, sarcoma, chronic sclerosing osteomyelitis, and temporomandibular joint disorders. • It can happen without exposure to these agents Ruggiero, S. L., et al. Medication-Related Osteonecrosis of the Jaw—AAOMS 2022 Update. Bisphosphonate Associated Osteonecrosis of the Jaw Courtesy: Hussam Batal DMD What is the risk for ONJ? • Among cancer patients exposed to zoledronate, the risk is ~ 1% (2-10X higher than cancer patients treated with placebo) • Among osteoporosis patients treated with oral bisphosphonates, the incidence is ≤0.05% (placebo 0-0.02%) • Risk for ONJ following tooth extraction is 0-0.15% • Higher risk with steroids, antiangiogenic agents, diabetes mellitus, tobacco use • Prevent ONJ with preventive dental care Ruggiero, S. L., et al. Medication-Related Osteonecrosis of the Jaw—AAOMS 2022 Update. Atypical Femoral Fractures Lenart et al, NEJM 359, 1305, 2008. Atypical Femoral Fracture Risk 2.3 per 10,000 person-years (FIT, FLEX, HORIZON-PFT) • 0.8 per 10,000 person-years (FIT) • 2.8 per 10,000 person-years (HORIZON-PFT) • 6.3 per 10,000 person-years (FLEX) May be associated with • Glucocorticoids, Proton pump inhibitors • Diabetes mellitus, Rheumatoid arthritis, hypophosphatasia, vitamin D deficiency Black et al. N Engl J Med 2010;362:1761-71; Shane et al, JBMR, Vol. 29:1-23, 2014. Benefits and Risks 30% 25% Includes 0.01% Atypical Femur Fracture Risk 25% 80 year-old woman with FN T-score = -3.3 20% 12.5% 15% Includes 0.5% Atypical Femur Fracture Risk 10% 5% 0.01% 0.11% ONJ Treated Fatal MVA 0.06% 0% Fx Risk Untreated Fx Risk Treated Murder Untreated probability of major osteoporotic fracture calculated by FRAX. ONJ estimate is ~1/100,000 patient-treatment-years from ASBMR Task Force by Khosla S et al. J Bone Miner Res 2007;22:1479–149. AFF estimate untreated is ~0.01/10,000 and treated is ~5/10,000 patient-years from Schilcher J et al. N Engl J Med. 2011;364:1728-1737. Risk estimates assume long-term bisphosphonate therapy resulting in 50% reduction in fracture risk. MVA and murder data from the CDC at http://www.cdc.gov/nchs/data/nvsr/nvsr56/nvsr56_10.pdf. Image copyright © 2017 Lewiecki EM. Slide version. What about tooth mobility? Antiresorptive therapy Bisphosphonate Calcitonin Anabolic therapy Teriparatide (PTH) Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Diravidamani et al, J Pharm Bioallied Sci. 2012 August; 4(Suppl 2): S299–S303. Hyperparathyroidism Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Case 42 yo woman with pain in the mandible Labs: Serum calcium 16.1 (8.2-10.2) mg/dl, PTH 1275 (1565) pg/ml, creatinine 0.84 (0.5-0.90) mg/dl Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Primary Hyperparathyroidism Brabyn, P.,et al. Journal of Oral and Maxillofacial Surgery 75, 2162–2169 (2017). Albright, F. JCEM (1948) 8:637. Painful bones, renal stones, abdominal groans, psychic moans, and fatigue overtones. Primary Hyperparathyroidism Majority caused by a single parathyroid adenoma Characterized by an elevated calcium and inappropriately normal or high parathyroid hormone Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Primary hyperparathyroidism (PHPT) Usually asymptomatic Symptoms Neuromuscular (fatigue, lethargy, weakness, depression, constipation) Cardiac (arrhythmias) Renal (polyuria, volume depletion, stones, calcinosis) Bone (osteoporosis) Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Risk Factors Prior head and neck irradiation Female Increasing age Genetic Multiple endocrine neoplasia (MEN 1, 2 and 4) Hyperparathyroidism Jaw Tumor syndrome Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine PHPT Natural History Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Rubin, M. R. et al. The Journal of Clinical Endocrinology & Metabolism 93, 3462–3470 (2008). Case 40 yo man with end-stage renal failure at age 35 on hemodialysis. Poor oral health with missing teeth, abundant plaque, calculus, dental stains and tooth decay. Significant dental mobility with displacement and gingival recession. Labs: Calcium normal (2.41 (2.18-2.58 mmol/l), Phosphate high (1.86 (0.8-1.5 mmol/l), PTH high 118 (11-54 pg/ml), and alkaline phosphatase 156 (35-100)IU/L. Benmoussa, L., et al. Journal of Oral and Maxillofacial Surgery 73, 2142–2148 (2015). Renal osteodystrophy Benmoussa, L., et al. Journal of Oral and Maxillofacial Surgery 73, 2142–2148 (2015). Chronic kidney disease 1. Decreased clearance of phosphate 2. FGF23 increases and decreases 1,25OHD production 3. As CKD progresses, decreased CYP27B1 Smit et al. Endocrine Reviews 40: 1468 – 1480, 2019 Secondary Hyperparathyroidism 1. Bone demineralization 2. Thinning or loss of cortical bone in multiple sites 3. Coarsened trabecular pattern 4. Osseus cysts (brown tumors) 5. Salt and pepper skull 6. Diffuse hypertrophy of maxilla and mandible 7. Serpentine channels You, M., et al. Oral Radiol 34, 262–266 (2018). Hypoparathyroidism Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Case 22 yo male with short stature, developmental delay, and seizure disorder. Kamarthi, N., et al. . Annals of Saudi Medicine 33, 411–413 (2013). Case: Seizures and short stature Labs: serum calcium 5.1 (9-11 mg/dl), phosphate 6.3 (3-5), PTH < 2.50 (14-72 pg/ml) Diagnosis: Hypoparathyroidism Dental findings: Enamel hypoplasia, short rounded roots, hypodontia, lack or delayed tooth eruption, partial anodontia and microdontia Kamarthi, N., et al. . Annals of Saudi Medicine 33, 411–413 (2013). Hypocalcemia Symptoms Acute Latent tetany Tetany Papilledema Seizures Chronic Cataracts Basal ganglia calcification Extrapyramidal disorders 66 Neuromuscular manifestations Tetany – occurs calcium 7-7.5 mg/dl Acid-base, K, Mg, epinephrine Carpopedal spasm, laryngospasm Trousseau’s sign/Chvostek’s sign Seizures Extrapyramidal disorders Papilledema Psychiatric manifestations/Intellectual impairment Myopathy 67 Chvostek’s Sign 68 Trousseau’s Sign 69 Ectodermal manifestations • Dry, puffy, coarse skin • Course, brittle, sparse hair with patchy alopecia; brittle nails with transverse grooves • Moniliasis (Type 1 PGA) Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine 70 Others • Ocular disease (cataracts) • Dental abnormalities • Cardiovascular disease –required for epinephrine-induced glycogenolysis in heart • Steatorrhea, achlorhydria • Decreased insulin release Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine 71 Osteomalacia Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Osteomalacia and rickets Altered bone mineralization and “softened bone” Painful bones Bowing of weight-bearing bones Can be genetic (X-linked hypophosphatemic osteomalacia, vitamin D dependent rickets, hypophosphatasia) or acquired (vitamin D deficiency, tumor-induced osteomalacia) Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Causes of Osteomalacia Vitamin D-related osteomalacia Severe vitamin D deficiency Vitamin D-dependent or – resistant rickets Calcium deficiency Hypophosphatemic osteomalacia Mineralization inhibitors: acidosis, aluminum, fluorosis, iron, etidronate, cadmium, strontium, hypophosphatasia Matrix abnormalities: Type VI OI, fibrogenesis imperfecta oss ium, axial osteomalacia Gastrointestinal causes Modified from Laurent et al. “Rickets and Osteomalacia” in 9th ed Primer Metab Bone Dis, ASBMR, 2019. Clinical Spectrum of Hypophosphatasia Diagnosed in Adults  N=22, F=15, M=7, mean age of dx = 49  Fam Hx: 2  Childhood rickets: 2  Symptoms: 15 with pain (thigh/hip, foot, back)  Fractures: 12  Femur/hip (4 AFF): 5  Feet: 5  Multiple fractures: 5  Chondrocalcinosis: 6  Pseudogout: 6  Dental:  Early baby tooth loss (3)  Thin enamel (1)  multiple extracted abnormal teeth (1)  Biochemistry:  Alkaline Phosphatase median 43% LLN (15%-98%)  Pyridoxal phosphate median 65 mcg/L (57140)  Phosphoethanolamine median 239 (157875) Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Berkseth et al, Bone, 2013; 54:21-27.  N=38,F=30, M=8  Muscle pain 61%  Headache 55%  39% H/O Fracture; 6 multiple  21% CPPD  47% Dental abnormalities  26% Early loss of permanent teeth  23% Enamel thin or severe caries  LS Z -0.2, FN Z -0.7  Alkaline phosphatase (LLN 35): 28.5  Bone specific alk phos (LLN 5.2) 3.8  Pyridoxal phosphate (<18.5) 49.9 T Schmidt et al. Osteoporos Int (2017) 28:2653–2662 Summary Part II Osteoporosis is a common cause of tooth loss Antiresorptive osteoporosis therapy is associated with osteonecrosis of the jaw Hyperparathyroidism, whether primary or secondary, causes alveolar bone loss and brown tumors Hypoparathyroidism may cause developmental problems Altered bone mineralization causes bone and tooth loss Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Questions? Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine Thank you for your attention! Boston Medical Center, Section of Endocrinology, Diabetes, Nutrition & Weight Management Boston University School of Medicine