Strict Phosphorus-Restricted Diet Causes Hypophosphatemic Osteomalacia in a Patient With Chronic Kidney Disease

Strict Phosphorus-Restricted Diet Causes Hypophosphatemic Osteomalacia in a Patient With Chronic... Abstract Patients with chronic kidney disease (CKD) need to follow phosphorus-restricted diets because impaired phosphorus excretion induces hyperphosphatemia in CKD, which increases mineral and bone disorders, cardiovascular diseases, and mortality; however, hypophosphatemic osteomalacia caused by phosphorus-restricted diets in CKD patients has not been described. We report here a patient with CKD in whom hypophosphatemia resulted in osteomalacia because of a phosphorus deficiency from a strict phosphorus-restricted diet. The patient (CKD stage G3b; estimated glomerular filtration rate, 31.5 mL/min/1.73 m2) presented with bone pain, muscle weakness, and multiple fragility fractures. She had been diagnosed with severe osteoporosis and treated with risedronate sodium and 1α-hydroxyvitamin D3 (alfacalcidol). Laboratory tests showed hypophosphatemia (1.7 mg/dL) with aphosphaturia; serum fibroblast growth factor 23 (FGF23) was <3 pg/mL. Radiological studies showed multiple fractures, and bone histology and morphometry of the iliac crest demonstrated a large amount of osteoid, with marked increases in all osteoid-associated parameters. Despite continuous administration of alfacalcidol, hypophosphatemic osteomalacia did not improve. The patient maintained a strict phosphorus-restricted diet, and laboratory examination indicated osteomalacia accompanied by phosphorus deficiency. Phosphorus supplementation improved her symptoms and pathological fractures in parallel with improved bone metabolic markers. Additionally, bone mineral density of the lumbar spine increased, suggesting calcification of unmineralized bone tissue. We conclude that this is a unique case of hypophosphatemic osteomalacia induced by a strict phosphorus-restricted diet and subsequent phosphorus deficiency in a patient with CKD. Histomorphometry revealed a marked increase in osteoid and phosphorus supplementation improved symptoms, fractures, and bone metabolic markers. Hypophosphatemia causes impaired bone mineralization, resulting in rickets and osteomalacia, which decrease bone density and increase bone fragility [1]. Patients with hypophosphatemic rickets/osteomalacia present with bone pain and muscle weakness occasionally complicating pathological fractures. The biochemical characteristic is elevation of serum alkaline phosphatase. Vitamin D deficiency and intestinal malabsorption are the most common causes, whereas increased renal tubular phosphate loss, including excess circulating fibroblast growth factor 23 (FGF23) and renal tubular disorders also result in development of hypophosphatemic rickets/osteomalacia [2]. Phosphorus restriction is an important nutritional treatment of mineral and bone disorders in chronic kidney disease (CKD-MBD). Elevation of serum phosphorus is associated with increased mortality in CKD-MBD [3]. Phosphorus retention occurs as a result of intestinal absorption exceeding renal excretion and/or dialysis removal. Dietary control of phosphorus load is helpful to preventing development of CKD-MBD, but dietary restriction is difficult because of the high phosphorus content in diets in developed countries today [4]. Thus, hypophosphatemic osteomalacia patients resulting from dietary restriction has not been described in CKD. We report here a patient with CKD in whom hypophosphatemia resulted in osteomalacia because of phosphorus deficiency caused by a strict phosphorus-restricted diet. 1. Case Report A 71-year-old Japanese woman with CKD developed bone pain, muscle weakness, and multiple fragility fractures of the hip, vertebrae, ulna, and tibia upon falling or after a slight collision. She became unable to walk or stand up by herself. She had been diagnosed with severe osteoporosis and treated with risedronate sodium (17.5 mg/wk) and 1α-hydroxyvitamin D3 (alfacalcidol) (0.5 µg/d) for at least 1 year; however, she had repeated fractures of various bones, regardless of these medications. She had no history of exposure to heavy metals, abdominal surgery, or treatment with phosphate binders, anticonvulsants, or antacids such as aluminum hydroxide. She had also no abnormal development or bone deformities in her childhood and adolescence, or bone metabolic diseases, such as congenital rachitic disorders, in her family history. The patient had been diagnosed with CKD of unknown cause 2 years ago, and had maintained a strict phosphorus-restricted diet composed of calcium (310 mg/d), phosphorus (600 mg/d), and vitamin D (160 IU/d). She washed and boiled all ingredients thoroughly and completely avoided high-phosphorus foods and those containing inorganic phosphorus as an additive. Laboratory tests showed normocalcemia (8.8 mg/dL; reference range, 7.0 to 10.0 mg/dL), hypophosphatemia (1.7 mg/dL; reference range, 2.9 to 4.3 mg/dL), and aphosphaturia (0 mg/d; reference range, 340 to 1000 mg/d). Furthermore, the 25-hydroxyvitamin D [25(OH)D] concentration was 9 ng/mL (reference range, 25 to 80 ng/mL) and FGF23 was <3 pg/mL (reference range, 8 to 54 pg/mL) (Table 1). Radiological studies revealed multiple fractures in the spine, ulna, tibia, and femur. Bone mineral density (BMD) of the lumbar spine (L2-L4) measured using dual energy X-ray absorptiometry was at the level of osteoporosis (T score, −2.5). Bone scintigraphy showed multiple hot spots, especially in the extremities and ribs [Fig. 1(b)]. The patient’s medical history and laboratory data suggested osteomalacia caused by phosphorus deficiency. To confirm this diagnosis, a transiliac bone biopsy was performed after double tetracycline labeling; the bone specimen was then methylmethacrylate-embedded using a nondecalcifying process. Bone histology and morphometry of the iliac crest demonstrated a large amount of osteoid, with marked increases in all osteoid-associated parameters, including osteoid volume, osteoid surface, and osteoid thickness. Various manifestations of mineralization defects, such as a few double, lamellar, thin, and thick single labels of tetracycline, were observed fluoroscopically (Fig. 2) (Table 2). Osteomalacia was diagnosed based on these specific bone tissue findings. Alfacalcidol was retained for treatment of vitamin D deficiency and risedronate was stopped. Furthermore, to treat phosphorus deficiency, administration of a neutral phosphorus mixture (elemental phosphorus, 2.0 g/day) was started after bone biopsy. After 2 weeks of phosphorus therapy, serum phosphate rose rapidly to 4.5 mg/dL and the phosphorus dose was reduced to 1.0 g/d [Fig. 1(a)]. Muscle weakness and bone pain resolved and the patient was able to sit up on the bed by herself. Consistent with the healing of osteomalacia, serum bone alkaline phosphatase gradually reached the normal range and serum FGF23 rose to 12.7 and 24.8 pg/mL at 1 and 6 months after phosphorus supplementation, respectively. Radiographs of the right femur showed pseudofracture on admission, with undisplaced radiolucent lines perpendicular to the femoral cortex, and healing of the pseudofracture 10 months after phosphorus treatment [Fig. 1(c)]. Multiple hot spots in bone scintigraphy also became light; moreover, BMD of the lumbar spine increased to the lower limit of the normal range (T score, −0.9). After treatment, the patient was able to walk with a cane. Table 1. Blood Chemistry Test and Urinalysis on Admission Before Phosphorus Supplementation     Reference Range      Reference Range  Blood chemistry test      Bone metabolic markers       Total protein, g/dL  5.8  6.5–8.5   Intact P1NP, µg/L  140  27.0–109.3   Albumin, g/dL  3.8  3.5–5.0   BAP, U/L  79.4  3.8–22.6   AST, U/L  15  13–33   BGP, ng/mL  8.8  3.1–12.7   ALT, U/L  10  6–27   TRACP-5b, mU/dL  682  120–420   ALP, U/L  638  115–359  Urinalysis   BUN, mg/dL  20  7–18   pH  8.0  5.0–7.5   Creatinine, mg/dL  1.31  0.4–0.9   Protein  —  —   eGFR, mL/min/1.73 m2  31.5  <90   Glucose  —  —   Ca, mg/dL  8.8  7.0–10.0   Blood  —  —   P, mg/dL  1.7  2.9–4.3   Ca, mg/d  102.6  100–300   PG, mg/dL  77  70–109   P, mg/d  0  340–1000  Endocrine test   Creatinine, mg/d  306  1000–2000   ACTH, pg/mL  31.3  7.2–63.3   %TRP  100  85–95   Cortisol, µg/dL  8.8  4.0–19.3   NAG, IU/L  23.6  1.0–12.0   FT4, pg/mL  1.43  0.9–1.7   β2MG, µg/L  13,886  16–518   TSH, µIU/mL  2.85  0.5–5.0   BJ protein  —  —   Whole PTH, pg/mL  33.9  9.0–39.0   Pan-aminoaciduria  —  —   1,25(OH)2D, pg/mL  42  20–60         25(OH)D, ng/mL  9  25–80         FGF23, pg/mL  <3  8–54            Reference Range      Reference Range  Blood chemistry test      Bone metabolic markers       Total protein, g/dL  5.8  6.5–8.5   Intact P1NP, µg/L  140  27.0–109.3   Albumin, g/dL  3.8  3.5–5.0   BAP, U/L  79.4  3.8–22.6   AST, U/L  15  13–33   BGP, ng/mL  8.8  3.1–12.7   ALT, U/L  10  6–27   TRACP-5b, mU/dL  682  120–420   ALP, U/L  638  115–359  Urinalysis   BUN, mg/dL  20  7–18   pH  8.0  5.0–7.5   Creatinine, mg/dL  1.31  0.4–0.9   Protein  —  —   eGFR, mL/min/1.73 m2  31.5  <90   Glucose  —  —   Ca, mg/dL  8.8  7.0–10.0   Blood  —  —   P, mg/dL  1.7  2.9–4.3   Ca, mg/d  102.6  100–300   PG, mg/dL  77  70–109   P, mg/d  0  340–1000  Endocrine test   Creatinine, mg/d  306  1000–2000   ACTH, pg/mL  31.3  7.2–63.3   %TRP  100  85–95   Cortisol, µg/dL  8.8  4.0–19.3   NAG, IU/L  23.6  1.0–12.0   FT4, pg/mL  1.43  0.9–1.7   β2MG, µg/L  13,886  16–518   TSH, µIU/mL  2.85  0.5–5.0   BJ protein  —  —   Whole PTH, pg/mL  33.9  9.0–39.0   Pan-aminoaciduria  —  —   1,25(OH)2D, pg/mL  42  20–60         25(OH)D, ng/mL  9  25–80         FGF23, pg/mL  <3  8–54        Abbreviations: 1,25(OH)2D, 1,25-dihydroxyvitamin D; ACTH, adrenocorticotropic hormone; ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; BAP, bone alkaline phosphatase; BGP, bone gla protein; BJ, Bence Jones; BUN, blood urea nitrogen; Ca, calcium; eGFR, estimated glomerular filtration rate; FT4, free thyroxine; NAG, N-acetyl-β-d-glucosaminidase; P, phosphate; PG, plasma glucose; P1NP, N-terminal propeptide of type I procollagen; PTH, parathyroid hormone; TRACP, Tartrate-resistant acid phosphatase; TRP, tubular reabsorption of phosphate; TSH, thyrotropin; β2MG, β-2-microglobulin. View Large Figure 1. View largeDownload slide (a) Timeline (weeks) of serum levels of calcium (mg/dL; open circles), phosphate (mg/dL; closed circles) and bone alkaline phosphatase (U/L; open squares), and the treatment of phosphorus and alfacalcidol (0.5 µg/d). (b) Bone scintigraphy with 99mTc-methylene diphosphonate revealed multiple hot spots, especially in the extremities and ribs, which were specific for osteomalacia on admission. After phosphorus supplementation, the hot spots became light in parallel with improvement of symptoms. (c) Radiographs of the right femur showed healing of the pseudofracture after 10 months. BAP, bone alkaline phosphatase; Ca, calcium; P, phosphate; IP, inorganic phosphorus. Figure 1. View largeDownload slide (a) Timeline (weeks) of serum levels of calcium (mg/dL; open circles), phosphate (mg/dL; closed circles) and bone alkaline phosphatase (U/L; open squares), and the treatment of phosphorus and alfacalcidol (0.5 µg/d). (b) Bone scintigraphy with 99mTc-methylene diphosphonate revealed multiple hot spots, especially in the extremities and ribs, which were specific for osteomalacia on admission. After phosphorus supplementation, the hot spots became light in parallel with improvement of symptoms. (c) Radiographs of the right femur showed healing of the pseudofracture after 10 months. BAP, bone alkaline phosphatase; Ca, calcium; P, phosphate; IP, inorganic phosphorus. Figure 2. View largeDownload slide Bone biopsy specimen from the iliac crest. The specimen was stained using Villanueva Bone Stain, methylmethacrylate-embedded, and sectioned. (a) Bone morphometry demonstrated abundant osteoid with a normal bone volume under natural light. (b) Mineralization defects such as few double, lamellar, thin, and thick single tetracycline labels were observed fluoroscopically. Figure 2. View largeDownload slide Bone biopsy specimen from the iliac crest. The specimen was stained using Villanueva Bone Stain, methylmethacrylate-embedded, and sectioned. (a) Bone morphometry demonstrated abundant osteoid with a normal bone volume under natural light. (b) Mineralization defects such as few double, lamellar, thin, and thick single tetracycline labels were observed fluoroscopically. Table 2. Bone Histomorphometry of Iliac Crest Parameter  Measured Value  Unit  Normal Range  BV/TV  24.5  %  19.56 ± 5.62  Tb.Th  174.2  µm  131.3 ± 28.1  W.Th  NA  µm  28.29 ± 3.74  OV/TV  10.8  %  0.36 ± 0.31  OV/BV  44.0  %  1.20 ± 0.87  OS/BS  85.0  %  14.0 ± 6.64  O.Th  45.0  µm  8.31 ± 1.99  ES/BS  14.4  %  3.66 ± 1.69  N.Oc/BS  1.56  N/mm  0.038–0.24  Fb.V/TV  0.19  %  0  MAR  0.34  µm/d  0.477 ± 0.078  Mlt  1399.9  Day  15.0 ± 50.6  dLS/BS  0.65  %  0.5–8.0  sLS/BS  14.6  %  0.5–10.5  BFR/BS  0.010  µm3/mm2/y  0.010 ± 0.008  BFR/BV  11.5  %/y  16.2 ± 12.5  Parameter  Measured Value  Unit  Normal Range  BV/TV  24.5  %  19.56 ± 5.62  Tb.Th  174.2  µm  131.3 ± 28.1  W.Th  NA  µm  28.29 ± 3.74  OV/TV  10.8  %  0.36 ± 0.31  OV/BV  44.0  %  1.20 ± 0.87  OS/BS  85.0  %  14.0 ± 6.64  O.Th  45.0  µm  8.31 ± 1.99  ES/BS  14.4  %  3.66 ± 1.69  N.Oc/BS  1.56  N/mm  0.038–0.24  Fb.V/TV  0.19  %  0  MAR  0.34  µm/d  0.477 ± 0.078  Mlt  1399.9  Day  15.0 ± 50.6  dLS/BS  0.65  %  0.5–8.0  sLS/BS  14.6  %  0.5–10.5  BFR/BS  0.010  µm3/mm2/y  0.010 ± 0.008  BFR/BV  11.5  %/y  16.2 ± 12.5  W.Th was not available because no basic structural units were seen on the bone biopsy specimen. Abbreviations: BFR/BS, bone formation rate/bone surface; BFR/BV, bone formation rate/bone volume; BV/TV, bone volume/tissue volume; dLS/BS, double labeled surface/bone surface; ES/BS, eroded surface/bone surface; Fb.V/TV, fibrosis volume/tissue volume; MAR, mineral apposition rate; Mlt, mineralization lag time; NA, not available; N.Oc/BS, osteoclast number/bone surface; OS/BS, osteoid surface/bone surface; O.Th, osteoid thickness; OV/BV, osteoid volume/bone volume; OV/TV, osteoid volume/tissue volume; sLS/BS, single labeled surface/bone surface; Tb.Th, trabecular thickness; W.Th, wall thickness. View Large 2. Discussion Phosphorus is important for growth plate maturation and skeletal mineralization, and rickets/osteomalacia accompanied by hypophosphatemia presents with skeletal abnormalities [2]. Hypophosphatemia results from excessive phosphorus loss (reduction of phosphorus reabsorption in the kidney or/and absorption in the gut) and insufficient phosphorus intake. Almost all hypophosphatemic rickets/osteomalacia, such as FGF23-related hypophosphatemic rickets/osteomalacia, Fanconi syndrome, vitamin D deficiency, and dependency, present with excessive phosphorus loss from the kidney and/or the gut [2]. Osteomalacia induced by depletion of phosphorus is easily produced in experimental animals [5]; however, this cause is very rare in humans. Phosphorus is ingested both as a natural component of food and as an additive. On average, about 60% of dietary phosphorus from natural food on average is absorbed in the intestine as inorganic phosphorus, whereas phosphorus originating from plants is absorbed less efficiently (<40%). Conversely, phosphorus salts added as food preservatives are almost completely absorbed (approaching 100%) [6, 7]. Currently, the quantity of phosphorus ingested from food is always sufficient because various phosphate salts are widely used as food additives. Excessive ingestion of phosphorus is regarded as an important problem in patients with CKD [3]. These patients tend to be positive in phosphorus balance because of impaired renal excretion, and thus are at increased risk for CKD-MBD, hospitalization, and cardiovascular mortality [3, 6]. Therefore, dietary restriction of phosphorus is crucial in nutritional treatment of CKD-MBD. Sixteen nondialyzed patients with CKD in whom protein and phosphorus restriction were followed long-term maintained normophosphatemia [8]. Two of these patients exhibited osteomalacia diagnosed by bone biopsy, but neither complained of any clinical symptoms such as bone pain or muscular weakness. In our patient, the presumed absorption of phosphorus was lower than the estimated phosphorus intake from her daily diet (600 mg/d) because almost all of her diet comprised natural food originating from plants, as well as being washed and boiled thoroughly to remove phosphorus in these ingredients. Aphosphaturia [resultantly 100% tubular reabsorption of phosphate (TRP)], calculated as %TRP = 100 × [1 − (urine phosphate/serum phosphate) / (urine creatinine/serum creatinine)] and undetectable FGF23 were also compatible with phosphorus deficiency. Vitamin D deficiency is the most common cause in patients with rickets/osteomalacia [9]. Serum parathyroid hormone (PTH) is negatively correlated with serum 25(OH)D [10]; thus, vitamin D deficiency causes secondary hyperparathyroidism in these patients, resulting in increased bone resorption and loss of bone density. Our patient was also diagnosed with vitamin D deficiency based on the low concentration of serum 25(OH)D; this caused a tendency for secondary hyperparathyroidism (whole PTH was at the upper limit of the normal range) and increased bone resorption. Despite alfacalcidol treatment before phosphorus supplementation, the patient exhibited persistent hypophosphatemic osteomalacia. The histomorphometry of the bone specimen showed not only a marked increase in osteoid, but also defective mineralization manifesting as irregular, attenuated, and less intense tetracycline labeling. Notably, phosphorus supplementation markedly resolved her symptoms and pathological fractures, consistent with fracture healing in phosphorus restriction models [5]. Bone metabolic markers also improved in parallel with her clinical recovery. This clinical course confirmed that phosphorus deficiency was essential for the impaired bone mineralization in this patient. Additionally, BMD of the lumbar spine was increased, most likely from calcification of unmineralized bone tissue by phosphorus supplementation. 3. Conclusion We have described a unique case of hypophosphatemic osteomalacia that was induced by a strict phosphorus-restricted diet and subsequent phosphorus deficiency in a patient with CKD. Histomorphometry revealed not only marked increased in osteoid, but also defective mineralization; treatment with phosphorus improved symptoms, fractures, and bone metabolic markers. Abbreviations: Abbreviations: 25(OH)D 25-hydroxyvitamin D BMD bone mineral density CKD chronic kidney disease CKD-MBD mineral and bone disorders in chronic kidney disease FGF23 fibroblast growth factor 23 PTH parathyroid hormone TRP tubular reabsorption of phosphate. Acknowledgments The authors thank Mrs. Akemi Ito and the Ito Bone Histomorphometry Institute for technical assistance. Disclosure Summary: The authors have nothing to disclose. References and Notes 1. Reginato AJ, Coquia JA. Musculoskeletal manifestations of osteomalacia and rickets. Best Pract Res Clin Rheumatol . 2003; 17( 6): 1063– 1080. Google Scholar CrossRef Search ADS PubMed  2. Fukumoto S. FGF23-FGF receptor/Klotho pathway as a new drug target for disorders of bone and mineral metabolism. Calcif Tissue Int . 2016; 98( 4): 334– 340. Google Scholar CrossRef Search ADS PubMed  3. Isakova T, Nickolas TL, Denburg M, Yarlagadda S, Weiner DE, Gutiérrez OM, Bansal V, Rosas SE, Nigwekar S, Yee J, Kramer H. KDOQI US commentary on the 2017 KDIGO Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Am J Kidney Dis . 2017; 70( 6): 737– 751. Google Scholar CrossRef Search ADS PubMed  4. Uenishi K, Ishimi Y, Nakamura K, Kodama H, Esashi T. Dietary reference intakes for Japanese 2010: macrominerals. J Nutr Sci Vitaminol (Tokyo) . 2013; 59( Suppl): S83– S90. Google Scholar CrossRef Search ADS   5. Wigner NA, Luderer HF, Cox MK, Sooy K, Gerstenfeld LC, Demay MB. Acute phosphate restriction leads to impaired fracture healing and resistance to BMP-2. J Bone Miner Res . 2010; 25( 4): 724– 733. Google Scholar PubMed  6. D’Alessandro C, Piccoli GB, Cupisti A. The “phosphorus pyramid”: a visual tool for dietary phosphate management in dialysis and CKD patients. BMC Nephrol . 2015; 16( 1): 9. Google Scholar CrossRef Search ADS PubMed  7. Moe SM, Zidehsarai MP, Chambers MA, Jackman LA, Radcliffe JS, Trevino LL, Donahue SE, Asplin JR. Vegetarian compared with meat dietary protein source and phosphorus homeostasis in chronic kidney disease. Clin J Am Soc Nephrol . 2011; 6( 2): 257– 264. Google Scholar CrossRef Search ADS PubMed  8. Lafage-Proust MH, Combe C, Barthe N, Aparicio M. Bone mass and dynamic parathyroid function according to bone histology in nondialyzed uremic patients after long-term protein and phosphorus restriction. J Clin Endocrinol Metab . 1999; 84( 2): 512– 519. Google Scholar CrossRef Search ADS PubMed  9. Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K, Michigami T, Tiosano D, Mughal MZ, Mäkitie O, Ramos-Abad L, Ward L, DiMeglio LA, Atapattu N, Cassinelli H, Braegger C, Pettifor JM, Seth A, Idris HW, Bhatia V, Fu J, Goldberg G, Sävendahl L, Khadgawat R, Pludowski P, Maddock J, Hyppönen E, Oduwole A, Frew E, Aguiar M, Tulchinsky T, Butler G, Högler W. Global consensus recommendations on prevention and management of nutritional rickets. J Clin Endocrinol Metab . 2016; 101( 2): 394– 415. Google Scholar CrossRef Search ADS PubMed  10. Garnero P, Sornay-Rendu E, Chapuy MC, Delmas PD. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Miner Res . 1996; 11( 3): 337– 349. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 Endocrine Society This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of the Endocrine Society Oxford University Press

Strict Phosphorus-Restricted Diet Causes Hypophosphatemic Osteomalacia in a Patient With Chronic Kidney Disease

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Abstract

Abstract Patients with chronic kidney disease (CKD) need to follow phosphorus-restricted diets because impaired phosphorus excretion induces hyperphosphatemia in CKD, which increases mineral and bone disorders, cardiovascular diseases, and mortality; however, hypophosphatemic osteomalacia caused by phosphorus-restricted diets in CKD patients has not been described. We report here a patient with CKD in whom hypophosphatemia resulted in osteomalacia because of a phosphorus deficiency from a strict phosphorus-restricted diet. The patient (CKD stage G3b; estimated glomerular filtration rate, 31.5 mL/min/1.73 m2) presented with bone pain, muscle weakness, and multiple fragility fractures. She had been diagnosed with severe osteoporosis and treated with risedronate sodium and 1α-hydroxyvitamin D3 (alfacalcidol). Laboratory tests showed hypophosphatemia (1.7 mg/dL) with aphosphaturia; serum fibroblast growth factor 23 (FGF23) was <3 pg/mL. Radiological studies showed multiple fractures, and bone histology and morphometry of the iliac crest demonstrated a large amount of osteoid, with marked increases in all osteoid-associated parameters. Despite continuous administration of alfacalcidol, hypophosphatemic osteomalacia did not improve. The patient maintained a strict phosphorus-restricted diet, and laboratory examination indicated osteomalacia accompanied by phosphorus deficiency. Phosphorus supplementation improved her symptoms and pathological fractures in parallel with improved bone metabolic markers. Additionally, bone mineral density of the lumbar spine increased, suggesting calcification of unmineralized bone tissue. We conclude that this is a unique case of hypophosphatemic osteomalacia induced by a strict phosphorus-restricted diet and subsequent phosphorus deficiency in a patient with CKD. Histomorphometry revealed a marked increase in osteoid and phosphorus supplementation improved symptoms, fractures, and bone metabolic markers. Hypophosphatemia causes impaired bone mineralization, resulting in rickets and osteomalacia, which decrease bone density and increase bone fragility [1]. Patients with hypophosphatemic rickets/osteomalacia present with bone pain and muscle weakness occasionally complicating pathological fractures. The biochemical characteristic is elevation of serum alkaline phosphatase. Vitamin D deficiency and intestinal malabsorption are the most common causes, whereas increased renal tubular phosphate loss, including excess circulating fibroblast growth factor 23 (FGF23) and renal tubular disorders also result in development of hypophosphatemic rickets/osteomalacia [2]. Phosphorus restriction is an important nutritional treatment of mineral and bone disorders in chronic kidney disease (CKD-MBD). Elevation of serum phosphorus is associated with increased mortality in CKD-MBD [3]. Phosphorus retention occurs as a result of intestinal absorption exceeding renal excretion and/or dialysis removal. Dietary control of phosphorus load is helpful to preventing development of CKD-MBD, but dietary restriction is difficult because of the high phosphorus content in diets in developed countries today [4]. Thus, hypophosphatemic osteomalacia patients resulting from dietary restriction has not been described in CKD. We report here a patient with CKD in whom hypophosphatemia resulted in osteomalacia because of phosphorus deficiency caused by a strict phosphorus-restricted diet. 1. Case Report A 71-year-old Japanese woman with CKD developed bone pain, muscle weakness, and multiple fragility fractures of the hip, vertebrae, ulna, and tibia upon falling or after a slight collision. She became unable to walk or stand up by herself. She had been diagnosed with severe osteoporosis and treated with risedronate sodium (17.5 mg/wk) and 1α-hydroxyvitamin D3 (alfacalcidol) (0.5 µg/d) for at least 1 year; however, she had repeated fractures of various bones, regardless of these medications. She had no history of exposure to heavy metals, abdominal surgery, or treatment with phosphate binders, anticonvulsants, or antacids such as aluminum hydroxide. She had also no abnormal development or bone deformities in her childhood and adolescence, or bone metabolic diseases, such as congenital rachitic disorders, in her family history. The patient had been diagnosed with CKD of unknown cause 2 years ago, and had maintained a strict phosphorus-restricted diet composed of calcium (310 mg/d), phosphorus (600 mg/d), and vitamin D (160 IU/d). She washed and boiled all ingredients thoroughly and completely avoided high-phosphorus foods and those containing inorganic phosphorus as an additive. Laboratory tests showed normocalcemia (8.8 mg/dL; reference range, 7.0 to 10.0 mg/dL), hypophosphatemia (1.7 mg/dL; reference range, 2.9 to 4.3 mg/dL), and aphosphaturia (0 mg/d; reference range, 340 to 1000 mg/d). Furthermore, the 25-hydroxyvitamin D [25(OH)D] concentration was 9 ng/mL (reference range, 25 to 80 ng/mL) and FGF23 was <3 pg/mL (reference range, 8 to 54 pg/mL) (Table 1). Radiological studies revealed multiple fractures in the spine, ulna, tibia, and femur. Bone mineral density (BMD) of the lumbar spine (L2-L4) measured using dual energy X-ray absorptiometry was at the level of osteoporosis (T score, −2.5). Bone scintigraphy showed multiple hot spots, especially in the extremities and ribs [Fig. 1(b)]. The patient’s medical history and laboratory data suggested osteomalacia caused by phosphorus deficiency. To confirm this diagnosis, a transiliac bone biopsy was performed after double tetracycline labeling; the bone specimen was then methylmethacrylate-embedded using a nondecalcifying process. Bone histology and morphometry of the iliac crest demonstrated a large amount of osteoid, with marked increases in all osteoid-associated parameters, including osteoid volume, osteoid surface, and osteoid thickness. Various manifestations of mineralization defects, such as a few double, lamellar, thin, and thick single labels of tetracycline, were observed fluoroscopically (Fig. 2) (Table 2). Osteomalacia was diagnosed based on these specific bone tissue findings. Alfacalcidol was retained for treatment of vitamin D deficiency and risedronate was stopped. Furthermore, to treat phosphorus deficiency, administration of a neutral phosphorus mixture (elemental phosphorus, 2.0 g/day) was started after bone biopsy. After 2 weeks of phosphorus therapy, serum phosphate rose rapidly to 4.5 mg/dL and the phosphorus dose was reduced to 1.0 g/d [Fig. 1(a)]. Muscle weakness and bone pain resolved and the patient was able to sit up on the bed by herself. Consistent with the healing of osteomalacia, serum bone alkaline phosphatase gradually reached the normal range and serum FGF23 rose to 12.7 and 24.8 pg/mL at 1 and 6 months after phosphorus supplementation, respectively. Radiographs of the right femur showed pseudofracture on admission, with undisplaced radiolucent lines perpendicular to the femoral cortex, and healing of the pseudofracture 10 months after phosphorus treatment [Fig. 1(c)]. Multiple hot spots in bone scintigraphy also became light; moreover, BMD of the lumbar spine increased to the lower limit of the normal range (T score, −0.9). After treatment, the patient was able to walk with a cane. Table 1. Blood Chemistry Test and Urinalysis on Admission Before Phosphorus Supplementation     Reference Range      Reference Range  Blood chemistry test      Bone metabolic markers       Total protein, g/dL  5.8  6.5–8.5   Intact P1NP, µg/L  140  27.0–109.3   Albumin, g/dL  3.8  3.5–5.0   BAP, U/L  79.4  3.8–22.6   AST, U/L  15  13–33   BGP, ng/mL  8.8  3.1–12.7   ALT, U/L  10  6–27   TRACP-5b, mU/dL  682  120–420   ALP, U/L  638  115–359  Urinalysis   BUN, mg/dL  20  7–18   pH  8.0  5.0–7.5   Creatinine, mg/dL  1.31  0.4–0.9   Protein  —  —   eGFR, mL/min/1.73 m2  31.5  <90   Glucose  —  —   Ca, mg/dL  8.8  7.0–10.0   Blood  —  —   P, mg/dL  1.7  2.9–4.3   Ca, mg/d  102.6  100–300   PG, mg/dL  77  70–109   P, mg/d  0  340–1000  Endocrine test   Creatinine, mg/d  306  1000–2000   ACTH, pg/mL  31.3  7.2–63.3   %TRP  100  85–95   Cortisol, µg/dL  8.8  4.0–19.3   NAG, IU/L  23.6  1.0–12.0   FT4, pg/mL  1.43  0.9–1.7   β2MG, µg/L  13,886  16–518   TSH, µIU/mL  2.85  0.5–5.0   BJ protein  —  —   Whole PTH, pg/mL  33.9  9.0–39.0   Pan-aminoaciduria  —  —   1,25(OH)2D, pg/mL  42  20–60         25(OH)D, ng/mL  9  25–80         FGF23, pg/mL  <3  8–54            Reference Range      Reference Range  Blood chemistry test      Bone metabolic markers       Total protein, g/dL  5.8  6.5–8.5   Intact P1NP, µg/L  140  27.0–109.3   Albumin, g/dL  3.8  3.5–5.0   BAP, U/L  79.4  3.8–22.6   AST, U/L  15  13–33   BGP, ng/mL  8.8  3.1–12.7   ALT, U/L  10  6–27   TRACP-5b, mU/dL  682  120–420   ALP, U/L  638  115–359  Urinalysis   BUN, mg/dL  20  7–18   pH  8.0  5.0–7.5   Creatinine, mg/dL  1.31  0.4–0.9   Protein  —  —   eGFR, mL/min/1.73 m2  31.5  <90   Glucose  —  —   Ca, mg/dL  8.8  7.0–10.0   Blood  —  —   P, mg/dL  1.7  2.9–4.3   Ca, mg/d  102.6  100–300   PG, mg/dL  77  70–109   P, mg/d  0  340–1000  Endocrine test   Creatinine, mg/d  306  1000–2000   ACTH, pg/mL  31.3  7.2–63.3   %TRP  100  85–95   Cortisol, µg/dL  8.8  4.0–19.3   NAG, IU/L  23.6  1.0–12.0   FT4, pg/mL  1.43  0.9–1.7   β2MG, µg/L  13,886  16–518   TSH, µIU/mL  2.85  0.5–5.0   BJ protein  —  —   Whole PTH, pg/mL  33.9  9.0–39.0   Pan-aminoaciduria  —  —   1,25(OH)2D, pg/mL  42  20–60         25(OH)D, ng/mL  9  25–80         FGF23, pg/mL  <3  8–54        Abbreviations: 1,25(OH)2D, 1,25-dihydroxyvitamin D; ACTH, adrenocorticotropic hormone; ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; BAP, bone alkaline phosphatase; BGP, bone gla protein; BJ, Bence Jones; BUN, blood urea nitrogen; Ca, calcium; eGFR, estimated glomerular filtration rate; FT4, free thyroxine; NAG, N-acetyl-β-d-glucosaminidase; P, phosphate; PG, plasma glucose; P1NP, N-terminal propeptide of type I procollagen; PTH, parathyroid hormone; TRACP, Tartrate-resistant acid phosphatase; TRP, tubular reabsorption of phosphate; TSH, thyrotropin; β2MG, β-2-microglobulin. View Large Figure 1. View largeDownload slide (a) Timeline (weeks) of serum levels of calcium (mg/dL; open circles), phosphate (mg/dL; closed circles) and bone alkaline phosphatase (U/L; open squares), and the treatment of phosphorus and alfacalcidol (0.5 µg/d). (b) Bone scintigraphy with 99mTc-methylene diphosphonate revealed multiple hot spots, especially in the extremities and ribs, which were specific for osteomalacia on admission. After phosphorus supplementation, the hot spots became light in parallel with improvement of symptoms. (c) Radiographs of the right femur showed healing of the pseudofracture after 10 months. BAP, bone alkaline phosphatase; Ca, calcium; P, phosphate; IP, inorganic phosphorus. Figure 1. View largeDownload slide (a) Timeline (weeks) of serum levels of calcium (mg/dL; open circles), phosphate (mg/dL; closed circles) and bone alkaline phosphatase (U/L; open squares), and the treatment of phosphorus and alfacalcidol (0.5 µg/d). (b) Bone scintigraphy with 99mTc-methylene diphosphonate revealed multiple hot spots, especially in the extremities and ribs, which were specific for osteomalacia on admission. After phosphorus supplementation, the hot spots became light in parallel with improvement of symptoms. (c) Radiographs of the right femur showed healing of the pseudofracture after 10 months. BAP, bone alkaline phosphatase; Ca, calcium; P, phosphate; IP, inorganic phosphorus. Figure 2. View largeDownload slide Bone biopsy specimen from the iliac crest. The specimen was stained using Villanueva Bone Stain, methylmethacrylate-embedded, and sectioned. (a) Bone morphometry demonstrated abundant osteoid with a normal bone volume under natural light. (b) Mineralization defects such as few double, lamellar, thin, and thick single tetracycline labels were observed fluoroscopically. Figure 2. View largeDownload slide Bone biopsy specimen from the iliac crest. The specimen was stained using Villanueva Bone Stain, methylmethacrylate-embedded, and sectioned. (a) Bone morphometry demonstrated abundant osteoid with a normal bone volume under natural light. (b) Mineralization defects such as few double, lamellar, thin, and thick single tetracycline labels were observed fluoroscopically. Table 2. Bone Histomorphometry of Iliac Crest Parameter  Measured Value  Unit  Normal Range  BV/TV  24.5  %  19.56 ± 5.62  Tb.Th  174.2  µm  131.3 ± 28.1  W.Th  NA  µm  28.29 ± 3.74  OV/TV  10.8  %  0.36 ± 0.31  OV/BV  44.0  %  1.20 ± 0.87  OS/BS  85.0  %  14.0 ± 6.64  O.Th  45.0  µm  8.31 ± 1.99  ES/BS  14.4  %  3.66 ± 1.69  N.Oc/BS  1.56  N/mm  0.038–0.24  Fb.V/TV  0.19  %  0  MAR  0.34  µm/d  0.477 ± 0.078  Mlt  1399.9  Day  15.0 ± 50.6  dLS/BS  0.65  %  0.5–8.0  sLS/BS  14.6  %  0.5–10.5  BFR/BS  0.010  µm3/mm2/y  0.010 ± 0.008  BFR/BV  11.5  %/y  16.2 ± 12.5  Parameter  Measured Value  Unit  Normal Range  BV/TV  24.5  %  19.56 ± 5.62  Tb.Th  174.2  µm  131.3 ± 28.1  W.Th  NA  µm  28.29 ± 3.74  OV/TV  10.8  %  0.36 ± 0.31  OV/BV  44.0  %  1.20 ± 0.87  OS/BS  85.0  %  14.0 ± 6.64  O.Th  45.0  µm  8.31 ± 1.99  ES/BS  14.4  %  3.66 ± 1.69  N.Oc/BS  1.56  N/mm  0.038–0.24  Fb.V/TV  0.19  %  0  MAR  0.34  µm/d  0.477 ± 0.078  Mlt  1399.9  Day  15.0 ± 50.6  dLS/BS  0.65  %  0.5–8.0  sLS/BS  14.6  %  0.5–10.5  BFR/BS  0.010  µm3/mm2/y  0.010 ± 0.008  BFR/BV  11.5  %/y  16.2 ± 12.5  W.Th was not available because no basic structural units were seen on the bone biopsy specimen. Abbreviations: BFR/BS, bone formation rate/bone surface; BFR/BV, bone formation rate/bone volume; BV/TV, bone volume/tissue volume; dLS/BS, double labeled surface/bone surface; ES/BS, eroded surface/bone surface; Fb.V/TV, fibrosis volume/tissue volume; MAR, mineral apposition rate; Mlt, mineralization lag time; NA, not available; N.Oc/BS, osteoclast number/bone surface; OS/BS, osteoid surface/bone surface; O.Th, osteoid thickness; OV/BV, osteoid volume/bone volume; OV/TV, osteoid volume/tissue volume; sLS/BS, single labeled surface/bone surface; Tb.Th, trabecular thickness; W.Th, wall thickness. View Large 2. Discussion Phosphorus is important for growth plate maturation and skeletal mineralization, and rickets/osteomalacia accompanied by hypophosphatemia presents with skeletal abnormalities [2]. Hypophosphatemia results from excessive phosphorus loss (reduction of phosphorus reabsorption in the kidney or/and absorption in the gut) and insufficient phosphorus intake. Almost all hypophosphatemic rickets/osteomalacia, such as FGF23-related hypophosphatemic rickets/osteomalacia, Fanconi syndrome, vitamin D deficiency, and dependency, present with excessive phosphorus loss from the kidney and/or the gut [2]. Osteomalacia induced by depletion of phosphorus is easily produced in experimental animals [5]; however, this cause is very rare in humans. Phosphorus is ingested both as a natural component of food and as an additive. On average, about 60% of dietary phosphorus from natural food on average is absorbed in the intestine as inorganic phosphorus, whereas phosphorus originating from plants is absorbed less efficiently (<40%). Conversely, phosphorus salts added as food preservatives are almost completely absorbed (approaching 100%) [6, 7]. Currently, the quantity of phosphorus ingested from food is always sufficient because various phosphate salts are widely used as food additives. Excessive ingestion of phosphorus is regarded as an important problem in patients with CKD [3]. These patients tend to be positive in phosphorus balance because of impaired renal excretion, and thus are at increased risk for CKD-MBD, hospitalization, and cardiovascular mortality [3, 6]. Therefore, dietary restriction of phosphorus is crucial in nutritional treatment of CKD-MBD. Sixteen nondialyzed patients with CKD in whom protein and phosphorus restriction were followed long-term maintained normophosphatemia [8]. Two of these patients exhibited osteomalacia diagnosed by bone biopsy, but neither complained of any clinical symptoms such as bone pain or muscular weakness. In our patient, the presumed absorption of phosphorus was lower than the estimated phosphorus intake from her daily diet (600 mg/d) because almost all of her diet comprised natural food originating from plants, as well as being washed and boiled thoroughly to remove phosphorus in these ingredients. Aphosphaturia [resultantly 100% tubular reabsorption of phosphate (TRP)], calculated as %TRP = 100 × [1 − (urine phosphate/serum phosphate) / (urine creatinine/serum creatinine)] and undetectable FGF23 were also compatible with phosphorus deficiency. Vitamin D deficiency is the most common cause in patients with rickets/osteomalacia [9]. Serum parathyroid hormone (PTH) is negatively correlated with serum 25(OH)D [10]; thus, vitamin D deficiency causes secondary hyperparathyroidism in these patients, resulting in increased bone resorption and loss of bone density. Our patient was also diagnosed with vitamin D deficiency based on the low concentration of serum 25(OH)D; this caused a tendency for secondary hyperparathyroidism (whole PTH was at the upper limit of the normal range) and increased bone resorption. Despite alfacalcidol treatment before phosphorus supplementation, the patient exhibited persistent hypophosphatemic osteomalacia. The histomorphometry of the bone specimen showed not only a marked increase in osteoid, but also defective mineralization manifesting as irregular, attenuated, and less intense tetracycline labeling. Notably, phosphorus supplementation markedly resolved her symptoms and pathological fractures, consistent with fracture healing in phosphorus restriction models [5]. Bone metabolic markers also improved in parallel with her clinical recovery. This clinical course confirmed that phosphorus deficiency was essential for the impaired bone mineralization in this patient. Additionally, BMD of the lumbar spine was increased, most likely from calcification of unmineralized bone tissue by phosphorus supplementation. 3. Conclusion We have described a unique case of hypophosphatemic osteomalacia that was induced by a strict phosphorus-restricted diet and subsequent phosphorus deficiency in a patient with CKD. Histomorphometry revealed not only marked increased in osteoid, but also defective mineralization; treatment with phosphorus improved symptoms, fractures, and bone metabolic markers. Abbreviations: Abbreviations: 25(OH)D 25-hydroxyvitamin D BMD bone mineral density CKD chronic kidney disease CKD-MBD mineral and bone disorders in chronic kidney disease FGF23 fibroblast growth factor 23 PTH parathyroid hormone TRP tubular reabsorption of phosphate. Acknowledgments The authors thank Mrs. Akemi Ito and the Ito Bone Histomorphometry Institute for technical assistance. Disclosure Summary: The authors have nothing to disclose. References and Notes 1. Reginato AJ, Coquia JA. Musculoskeletal manifestations of osteomalacia and rickets. Best Pract Res Clin Rheumatol . 2003; 17( 6): 1063– 1080. Google Scholar CrossRef Search ADS PubMed  2. Fukumoto S. FGF23-FGF receptor/Klotho pathway as a new drug target for disorders of bone and mineral metabolism. Calcif Tissue Int . 2016; 98( 4): 334– 340. Google Scholar CrossRef Search ADS PubMed  3. Isakova T, Nickolas TL, Denburg M, Yarlagadda S, Weiner DE, Gutiérrez OM, Bansal V, Rosas SE, Nigwekar S, Yee J, Kramer H. KDOQI US commentary on the 2017 KDIGO Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Am J Kidney Dis . 2017; 70( 6): 737– 751. Google Scholar CrossRef Search ADS PubMed  4. Uenishi K, Ishimi Y, Nakamura K, Kodama H, Esashi T. Dietary reference intakes for Japanese 2010: macrominerals. J Nutr Sci Vitaminol (Tokyo) . 2013; 59( Suppl): S83– S90. Google Scholar CrossRef Search ADS   5. Wigner NA, Luderer HF, Cox MK, Sooy K, Gerstenfeld LC, Demay MB. Acute phosphate restriction leads to impaired fracture healing and resistance to BMP-2. J Bone Miner Res . 2010; 25( 4): 724– 733. Google Scholar PubMed  6. D’Alessandro C, Piccoli GB, Cupisti A. The “phosphorus pyramid”: a visual tool for dietary phosphate management in dialysis and CKD patients. BMC Nephrol . 2015; 16( 1): 9. Google Scholar CrossRef Search ADS PubMed  7. Moe SM, Zidehsarai MP, Chambers MA, Jackman LA, Radcliffe JS, Trevino LL, Donahue SE, Asplin JR. Vegetarian compared with meat dietary protein source and phosphorus homeostasis in chronic kidney disease. Clin J Am Soc Nephrol . 2011; 6( 2): 257– 264. Google Scholar CrossRef Search ADS PubMed  8. Lafage-Proust MH, Combe C, Barthe N, Aparicio M. Bone mass and dynamic parathyroid function according to bone histology in nondialyzed uremic patients after long-term protein and phosphorus restriction. J Clin Endocrinol Metab . 1999; 84( 2): 512– 519. Google Scholar CrossRef Search ADS PubMed  9. Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K, Michigami T, Tiosano D, Mughal MZ, Mäkitie O, Ramos-Abad L, Ward L, DiMeglio LA, Atapattu N, Cassinelli H, Braegger C, Pettifor JM, Seth A, Idris HW, Bhatia V, Fu J, Goldberg G, Sävendahl L, Khadgawat R, Pludowski P, Maddock J, Hyppönen E, Oduwole A, Frew E, Aguiar M, Tulchinsky T, Butler G, Högler W. Global consensus recommendations on prevention and management of nutritional rickets. J Clin Endocrinol Metab . 2016; 101( 2): 394– 415. Google Scholar CrossRef Search ADS PubMed  10. Garnero P, Sornay-Rendu E, Chapuy MC, Delmas PD. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Miner Res . 1996; 11( 3): 337– 349. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 Endocrine Society This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).

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Journal of the Endocrine SocietyOxford University Press

Published: Feb 1, 2018

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