TY - JOUR
AU - Yalla,, Naga
AB - Case Description A 58-year-old Caucasian woman was referred to the University Bone Health Program for evaluation. Her past medical history was significant for Roux-en-Y gastric bypass (RYGB)2 surgery 10 years previously, following which she lost 100 pounds, but she regained weight thereafter, for a net weight loss of 20 pounds (current body mass index 44 kg/m2). In addition, she had a history of hypothyroidism, osteoarthritis, and esophageal ulcers. Eight months before her visit, she sustained bilateral pubic rami fractures following a fall from standing height. A few months later, she complained of worsening pelvic pain. At that time, a magnetic resonance image revealed sacral insufficiency fractures. She was diagnosed with vitamin D deficiency (25-OH vitamin D concentration <13 ng/mL [30–100 ng/mL]) and hypocalcemia (total serum calcium 8.1 mg/dL [8.6–10.4 mg/dL] with normal serum albumin). She had been taking 1200 mg of calcium citrate per day, but 50000 IUs of vitamin D (cholecalciferol) once weekly was prescribed in addition. On the basis of a presumed diagnosis of osteoporosis, she was also prescribed 150 mg of ibandronate (Boniva®) once monthly. Her reproductive history included menarche at age 14 and a hysterectomy at age 33, for which she had taken hormone replacement therapy ever since (Premarin® 1.25 mg daily). Other pertinent medications included omeprazole (a proton pump inhibitor). A review of systems was positive for a constellation of symptoms, including diffuse dull aching bony pain, fatigue, decreased muscle strength, and increasing gait instability with frequent falls. Her laboratory tests revealed a microcytic anemia, with subsequent iron studies confirming iron deficiency. Pertinent laboratory test results are listed in Table 1. Of note, her vitamin B12, vitamin A, folic acid, and zinc concentrations were within the respective reference intervals. Table 1. Initial laboratory results. Test (reference interval) . Result . Serum calcium (8.6–10.4 mg/dL) 8.7 Parathyroid hormone (10–65 pg/mL) 175 25-OH vitamin D (30–100 ng/mL) 28 Alkaline phosphatase (33–130 IU/L) 182 24-h urine calcium (25–300 mg/day) 108 Test (reference interval) . Result . Serum calcium (8.6–10.4 mg/dL) 8.7 Parathyroid hormone (10–65 pg/mL) 175 25-OH vitamin D (30–100 ng/mL) 28 Alkaline phosphatase (33–130 IU/L) 182 24-h urine calcium (25–300 mg/day) 108 Open in new tab Table 1. Initial laboratory results. Test (reference interval) . Result . Serum calcium (8.6–10.4 mg/dL) 8.7 Parathyroid hormone (10–65 pg/mL) 175 25-OH vitamin D (30–100 ng/mL) 28 Alkaline phosphatase (33–130 IU/L) 182 24-h urine calcium (25–300 mg/day) 108 Test (reference interval) . Result . Serum calcium (8.6–10.4 mg/dL) 8.7 Parathyroid hormone (10–65 pg/mL) 175 25-OH vitamin D (30–100 ng/mL) 28 Alkaline phosphatase (33–130 IU/L) 182 24-h urine calcium (25–300 mg/day) 108 Open in new tab QUESTIONS TO CONSIDER What is the most likely diagnosis in this patient? What mechanisms explain the effects of bariatric surgery on skeletal health? What is the best long-term management of this patient? Bone densitometry determined by dual-energy x-ray absorptiometry revealed the following T-scores: lumbar spine (L1–L4) was −0.7, total hip was −1.2, and left femoral neck was −1.2. For diagnostic purposes, values above −1.0 are considered normal, from −1.0 to −2.5 suggest osteopenia, and less than −2.5 suggest osteoporosis. Obesity has emerged as a global epidemic. In the US alone, 1 in 20 adults suffers from extreme obesity, defined as a body mass index >40 kg/m2 (1) Bariatric surgery has emerged as an effective treatment for patients with severe obesity, often producing durable weight loss and attendant improvements in the metabolic complications associated with obesity (including hypertension, diabetes mellitus, and obstructive sleep apnea), as well as a decrease in mortality. Bariatric surgery procedures are generally classified as being restrictive (e.g., sleeve gastrectomy and adjustable gastric banding) or malabsorptive [e.g., biliopancreatic diversions (BPD)]. RYGB is considered to be a combination of restrictive and malabsorptive procedures. The RYGB involves the creation of a 30-mL proximal gastric pouch that is anastomosed directly to the proximal jejunum, thus bypassing the greater portion of the stomach and duodenum. This results both in a narrow anastomotic outlet, which serves to restrict caloric intake, and a substantial decrease in the intestinal surface area available for caloric absorption. In the long term, however, the procedure often results in the malabsorption of necessary minerals and fat-soluble vitamins (2). Sleeve gastrectomies are a relatively new procedure, but have surpassed RYGB as the most popular bariatric technique (3). Though bariatric surgery appears to be beneficial from a cardiometabolic standpoint, there is emerging concern regarding the negative impact of these surgeries on long-term skeletal health, particularly malabsorptive and mixed procedures like RYGB. Recent studies have demonstrated an increase in bone turnover markers and declines in bone mineral density following these procedures (2, 4). Initially, bone loss was attributed primarily to nutritional deficiencies (which can range from malabsorption to frank osteomalacia) and the effects of skeletal unloading due to weight loss. However, in the last decade, pioneering work by bone biologists has pointed to a complex “cross talk” among adipocytes, the skeletal system, and the gastrointestinal system. These neurohormonal changes have been implicated as potential mediators of bone loss (2, 4). POINTS TO REMEMBER Bariatric surgery is one of the most effective means to treat obesity. While many of the cardio-metabolic complications associated with obesity may resolve with bariatric surgery, there may be long-term adverse skeletal effects. Skeletal impact is most apparent in malabsorptive procedures (i.e., RYGB) and BPD. The mechanisms by which bone loss occurs are complex and multifactorial, including nutritional deficiencies of calcium and vitamin D, mechanical unloading produced by weight loss, and complex neurohormonal changes. Osteomalacia can manifest as generalized bone pain, muscle weakness, bony tenderness, low-trauma fractures, altered gait, and in severe cases with symptoms and signs of hypocalcemia. Laboratory manifestations include decreased 25-OH vitamin D concentration, increased PTH concentration, and increased alkaline phosphatase activity. Some patients may also exhibit decreased serum calcium, serum phosphorus, and 24-h urinary calcium excretion. Recognition of nutritional deficiencies and skeletal impact of bariatric surgeries has led to guidelines that advocate preoperative assessments of 25-OH vitamin D and aggressive postoperative calcium and vitamin D supplementation. DIAGNOSIS Given the patient's clinical presentation, history of low-trauma fractures, hypocalcemia, persistently increased serum alkaline phosphatase, and evidence of secondary hyperparathyroidism, the primary diagnosis was identified as osteomalacia, caused by chronic malabsorption of calcium and vitamin D in the setting of a prior RYGB and further exacerbated by chronic proton pump inhibitor use. Her initial laboratory studies, performed 6 months after she was started on high-dose vitamin D supplementation, did not convey the severity of her underlying osteomalacia. This case highlights the importance of differentiating osteomalacia from the more common disorder of osteoporosis, which can also increase fracture risk in postmenopausal women. PROPOSED MECHANISMS OF BONE LOSS FOLLOWING BARIATRIC SURGERY Over the last 2 decades, understanding of the etiology of bone loss after bariatric procedures has evolved. Changes in the pattern of bone turnover markers suggest a shift in bone remodeling that favors resorption (breakdown) vs bone formation. Markers of resorption, including serum and urinary C-terminal telopeptide and urinary N-terminal telopeptide, and markers of bone formation, including osteocalcin, procollagen I intact N-terminal propeptide, and bone-specific alkaline phosphatase, begin to rise as early as 3 months postoperatively, and the increases in some studies appear to persist beyond the first postoperative year, even after correction of nutritional deficiencies and stabilization of weight loss (4, 5). Some studies have suggested an increase of 60%–200% in bone resorption markers with gastric bypass procedures (6). This increased resorption may account for the continued and ongoing declines in bone mineral density demonstrated in multiple longitudinal studies. These declines appear to be more pronounced in the hip, with some studies demonstrating concurrent declines in the lumbar spine density measurements as well (4, 5). Studies thus far have shown conflicting results regarding whether the increase in bone turnover and declines in bone mineral density measurements translate to an increased risk of fracture. A retrospective study performed by the Rochester Epidemiology Project suggested a 2-fold higher risk of fractures in patients (n = 258) who had undergone bariatric procedures when compared to community based incidence rates. The mean follow-up time was 8.9 years, and 75% of patients had undergone RYGB (7). However, in a larger retrospective case–control study from Quebec (n = 12676), only BPD were clearly associated with an increased fracture risk, with no statistically significant increased incidence of fracture risk noted in the subset of patients in the RYGB group (8). The etiology for the increased resorption, declines in bone mass, and the potential increase in fracture risk is likely multifactorial. Explanations include nutritional deficiencies, skeletal unloading from weight loss, and possibly alterations of the neurohormonal milieu arising from alterations in body composition. Nutritional deficiencies are common in patients undergoing bariatric procedures, particularly malabsorptive procedures like the BPD and RYGB, which result in chronic malabsorption of calcium and vitamin D. RYGB procedures bypass the duodenum and proximal jejunum, where it is estimated that 80% of calcium absorption occurs. These procedures, with concurrent proton pump inhibitor use, which are common in these patients, may also limit gastric acid production and negatively impact calcium absorption. Additionally, the jejunum is a critical site for vitamin D absorption, which is facilitated by bile acids and pancreatic enzymes, and which may be compromised in duodenal exclusion procedures. Most studies to date have demonstrated increased parathyroid hormone (PTH) concentrations and decreased urinary calcium, consistent with calcium malabsorption. The increased PTH facilitates increased calcium absorption from the gut and renal tubular system, and increased bone resorption over time. Essentially, as the body attempts to maintain normal calcium homeostasis, it does so at the expense of the skeleton (6, 9). Patients are also at risk for protein malnutrition, vitamin B12, vitamin A, folic acid, and iron deficiency. Over time, untreated, this can lead to osteomalacia, a disorder characterized by decreased mineralization of osteoid. Clinically, osteomalacia can manifest as generalized bone pain, muscle weakness, bony tenderness, low-trauma fractures, altered gait, and, in severe cases, with hypocalcemia. The biochemical manifestations include low 25-OH vitamin D concentration, increased PTH concentration, and increased alkaline phosphatase activity. Some patients may additionally exhibit decreased serum calcium and phosphorus concentrations and decreased 24-h urinary calcium excretion. Radiographic findings may include decreased bone density and Looser zones/pseudofractures, which are considered pathognomonic of osteomalacia. Bone biopsy with tetracycline labeling offers the most definitive means of diagnosing osteomalacia, though rarely used as the diagnosis can be frequently established on the basis of the clinical presentation and appropriate laboratory evaluation. Skeletal unloading secondary to significant weight loss may also account for the decreases in bone mineral density in these patients. Loss of mechanical loading can result in bone loss, mediated by increased sclerostin production. Sclerostin negatively regulates canonical Wnt signaling, resulting in decreased osteoblast differentiation and function and may contribute to decreased bone formation (2). The hip, which carries a load 2 to 3 times body weight, may be preferentially affected by weight loss, and this may account for the large declines in hip bone mineral density measurements seen in most studies (5). Animal models and human data suggest that the increase in bone turnover markers, particularly resorption markers, appear to persist despite stabilization in weight loss and correction of nutritional deficiencies, suggesting that mechanical unloading and nutritional factors are not the sole factors driving bone loss. Over the last several years, understanding of the complex crosstalk between the bone, gut, and adipose tissue has increased. This knowledge has been largely derived from rodent models, which have established the effects of the adipokines, leptin and adiponectin, on bone metabolism. Recent data have also implicated serotonin, glucagon like peptide-1 (GLP1), ghrelin, and gastric inhibitory polypeptide (GIP) as potentially impacting skeletal health (2, 4). It is possible that the changes in body composition and the attendant neurohormonal changes may account for the skeletal changes witnessed after bariatric procedures. This remains an avenue for future research. CLINICAL MANAGEMENT AND COURSE The patient was aggressively treated with high-dose cholecalciferol (vitamin D3) 50000 IU twice weekly in addition to 5000 IU cholecalciferol daily. In addition, her calcium supplementation was doubled to 2400 mg calcium citrate daily. In our patient's case, the previous diagnosis had been osteoporosis, so she had been prescribed bisphosphonate therapy, which inhibits osteoclast activity and bone resorption. However, bisphosphonates are contraindicated in patients with osteomalacia, as they could exacerbate hypocalcemia and interfere with skeletal remineralization. There is also concern that oral bisphosphonates could increase the risk of reflux and anastomotic ulceration in bypass patients (5). Thus, the patient's oral bisphosphonate was discontinued. Over the next several months, her biochemical parameters improved (Table 2). Her serum alkaline phosphatase and serum calcium normalized, and her PTH trended downward but failed to entirely normalize. The patient continued to sustain low-trauma fractures including an interval sternal fracture, but after 1 year of treatment she reported no further fractures. Her bony pain significantly improved, and her lumbar spine bone mineral density stabilized with a 7% statistically significant improvement in the hip bone mineral density 2 years later. Table 2. Follow-up testing. Test (reference interval) . Months after initial presentation . 2 . 3 . 6 . 11 . 13 . 26 . 30 . 34 . Serum calcium (8.6–10.4 mg/dL) 8.2 9.2 9.3 9.4 9.4 Parathyroid hormone (10–65 pg/mL) 218 162 120 167 120 120 82 25-OH vitamin D (30–100 ng/mL) 27 20 48 50 56 65 Alkaline phosphatase (33–130 IU/L) 150 137 127 124 117 123 24-h urine calcium (25–300 mg/day) 113 123 176 Test (reference interval) . Months after initial presentation . 2 . 3 . 6 . 11 . 13 . 26 . 30 . 34 . Serum calcium (8.6–10.4 mg/dL) 8.2 9.2 9.3 9.4 9.4 Parathyroid hormone (10–65 pg/mL) 218 162 120 167 120 120 82 25-OH vitamin D (30–100 ng/mL) 27 20 48 50 56 65 Alkaline phosphatase (33–130 IU/L) 150 137 127 124 117 123 24-h urine calcium (25–300 mg/day) 113 123 176 Open in new tab Table 2. Follow-up testing. Test (reference interval) . Months after initial presentation . 2 . 3 . 6 . 11 . 13 . 26 . 30 . 34 . Serum calcium (8.6–10.4 mg/dL) 8.2 9.2 9.3 9.4 9.4 Parathyroid hormone (10–65 pg/mL) 218 162 120 167 120 120 82 25-OH vitamin D (30–100 ng/mL) 27 20 48 50 56 65 Alkaline phosphatase (33–130 IU/L) 150 137 127 124 117 123 24-h urine calcium (25–300 mg/day) 113 123 176 Test (reference interval) . Months after initial presentation . 2 . 3 . 6 . 11 . 13 . 26 . 30 . 34 . Serum calcium (8.6–10.4 mg/dL) 8.2 9.2 9.3 9.4 9.4 Parathyroid hormone (10–65 pg/mL) 218 162 120 167 120 120 82 25-OH vitamin D (30–100 ng/mL) 27 20 48 50 56 65 Alkaline phosphatase (33–130 IU/L) 150 137 127 124 117 123 24-h urine calcium (25–300 mg/day) 113 123 176 Open in new tab Recognition of the nutritional deficiencies and skeletal impact of bariatric surgery has led to American Association of Clinical Endocrinologists/The Obesity Society/American Society for Metabolic and Bariatric Surgery and Endocrine Society guidelines to advocate preoperative assessments of 25-OH vitamin D concentrations and aggressive calcium and vitamin D supplementation. Postoperatively, the guidelines suggest that patients who have undergone malabsorptive surgical procedures should have 25-OH vitamin D, calcium, phosphorus, PTH, and alkaline phosphatase every 6 months following and have dual-energy x-ray absorptiometry for bone density performed every 1–2 years until stable (10, 11). 2 Nonstandard abbreviations RYGB Roux-en-Y gastric bypass BPD biliopancreatic diversions PTH parathyroid hormone. " Author Contributions:All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. " Authors' Disclosures or Potential Conflicts of Interest:No authors declared any potential conflicts of interest. References 1. Flegal KM , Carroll MD, Kit BK, Ogden CL . 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Google Scholar Crossref Search ADS PubMed WorldCat © 2018 The American Association for Clinical Chemistry This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Bad Breaks
JO - Clinical Chemistry
DO - 10.1373/clinchem.2017.279430
DA - 2018-01-01
UR - https://www.deepdyve.com/lp/oxford-university-press/bad-breaks-sMXQMStos0
SP - 47
VL - 64
IS - 1
DP - DeepDyve
ER -