Osteomalacia and Rickets

Definition

Rickets can no longer be considered a historical disorder limited to third world countries or poor people. The COVID-19 pandemic and the loss of school dairy products in the United States has increased malnutrition and vitamin D deficiency. The primary function of vitamin D is to provide adequate levels of calcium and phosphorus by increasing their intestinal absorption, thereby making them available for normal mineralization of bone and epiphyseal cartilage. Rickets, which occurs in growing children, affects both the cartilaginous growth plate and bone, where it causes characteristic deformities. Osteomalacia, which occurs after growth has ceased, has more subtle manifestations that are frequently overlooked.

Normal mineralization requires the availability of sufficient calcium and phosphorus, the presence of normal bone collagen, the absence of inhibitors of mineralization, and an adequate amount of bone alkaline phosphatase activity. Defects in these requirements are the cause of most forms of osteomalacia. Deficiency of vitamin D in isolation has traditionally been incriminated as the cause of the osteomalacia, but today, considerable evidence indicates that the abnormal mineralization associated with vitamin D deficiency is due to inadequate calcium and phosphorus rather than the absence of a direct effect of vitamin D on bone cells. Optimal therapy requires precise identification of the etiology of the abnormal mineralization ( Table 226-1 ), and thereby is often gratifying.

Epidemiology

Nutritional rickets continues to be an evolving and multifactorial problem worldwide. ^, About 25% of women in the United States have 25-hydroxyvitamin D levels below 20 ng/mL (adequate values are greater than 30 ng/mL), and 8% have levels below 12 ng/mL, thereby indicating that impaired bone mineralization could be a confounding factor in the treatment of their osteoporosis and that osteomalacia (defective mineralization) rather than osteoporosis (reduced amount of normally mineralized bone) is the underlying problem.

Osteomalacia and vitamin D deficiency must be excluded before administration of the antiresorptive drugs used for postmenopausal osteoporosis ( Chapter 225 ), particularly before the use of zoledronate or denosumab, which will induce hypocalcemia and secondary hyperparathyroidism if vitamin D levels are inadequate. Vitamin D deficiency is a particular problem in the nonaffluent elderly and individuals with self-imposed diets that avoid meat, dairy products, and fish. Vitamin D deficiency is also commonly found in medical inpatients and in postmenopausal women with an acute hip fracture. The prevalence of osteomalacia due to vitamin D deficiency varies; at greatest risk are incarcerated patients, patients with cystic fibrosis ( Chapter 77 ), gastric bypass surgery ( Chapter 201 ), or patients who have hyperparathyroidism ( Chapter 227 ), that is actually secondary to vitamin D deficiency. Also at risk are individuals who live in chronic care facilities or who have nonhealing fractures.

X-linked hypophosphatemia, which is the most common inherited form of hypophosphatemic osteomalacia, has a prevalence of 1:20,000.

Pathobiology

The abnormal mineralization characteristic of osteomalacia is due to slowed or terminated mineral deposition in the organic matrix of bone (osteoid) because of one or more of the defects mentioned earlier. However, osteoblasts continue to make osteoid, which then accumulates in excessive amounts. Histologically, the osteoid width may become dramatically augmented ( Fig. 226-1 ). Depending on the extent of the mineralization delay, overt osteomalacia may take many years to develop. After normalization of the serum calcium and phosphorus levels, bone healing may take at least 6 to 18 months.

X-linked hypophosphatemia, hypophosphatemic rickets, and tumor-induced osteomalacia are due to increased (or inappropriate for the low serum phosphate) serum fibroblast growth factor 23 (FGF-23) levels that cause excessive phosphaturia and inhibition of 25-hydroxyvitamin D-1α-hydroxylase. The hypophosphatemia is intensified by the inappropriately low levels of 1,25-dihydroxyvitamin D. Tumor-induced osteomalacia is a rare form of acquired, paraneoplastic, hypophosphatemic osteomalacia due to prostatic adenocarcinoma ( Chapter 186 ), other metastatic tumors, and small and often hard-to-find benign mesenchymal tumors ( Chapter 187 ).

Hypophosphatemic osteomalacia and fractures may occur after the administration of intravenous ferric carboxymaltose for refractory iron deficiency anemia. The hypophosphatemia may be detected within 1 week of the infusion, persist, and be accompanied by a two- to four-fold increase in FGF-23. This complication does not occur with administration of ferumoxytol.

Osteomalacia also can be caused by inhibitors of mineralization such as etidronate (the first oral bisphosphonate, now rarely used in North America), high doses of fluoride (in bulk tea), the accumulation of a skeletal burden of aluminum from water used for dialysis (now rarely seen), iron overload as in thalassemia, and from high pyrophosphate levels in hypophosphatasia. Cholestyramine therapy for cholestasis or laxative abuse may also cause malabsorption and resistance to vitamin D supplements. Cadmium, tenofovir, or adefovir may induce Fanconi syndrome and cause osteomalacia due to the resultant hypophosphatemia.

Several presumed causes of osteomalacia (anticonvulsant drugs, metabolic acidosis without hypophosphatemia, pseudohypoparathyroidism, and chronic renal failure) have not demonstrated accumulation of osteoid due to delayed mineralization and primarily represent secondary hyperparathyroidism. Patients with the nephrotic syndrome lose albumin and vitamin D metabolites in the urine, but their serum ionized calcium and PTH levels are normal and metabolic bone disease in adults with the nephrotic syndrome is absent unless glucocorticoids have been administered.

Clinical Manifestations

The clinical presentation of osteomalacia depends on three overlapping manifestations: those due to the underlying disorder such as gastrointestinal disease or surgery (especially troublesome are gastric resection, or gastric bypass for obesity [ Chapter 201 ], celiac disease [ Chapter 126 ], and intestinal malabsorption [ Chapter 126 ]); those due to hypocalcemia or hypophosphatemia; and those directly due to the bone disease.

The most common symptoms and signs are pain in the pelvis and legs, muscle weakness, and bone tenderness. Bone pain is usually nonspecific and poorly localized. Because of the paucity of findings, the pains are often attributed to rheumatism or neurosis. Bone pain may be worse at night and after sudden movements, such as turning in bed or the change from sitting to standing.

The pain is worse on weight bearing, thereby resulting in a characteristic flat-footed, springless, waddling gait made worse by proximal muscle weakness. The gait has been referred to as “mother penguin’s walk.” Patients may complain that they can climb stairs only by pulling themselves up with the hand rail or rise from a chair or the toilet by using their hands to push off. The decrease in strength is usually far greater than the degree of muscle wasting.

Fasciculations are absent, and both reflexes and sensation remain normal. The bulbar, facial, and ocular muscles are always spared.

In X-linked hypophosphatemia, the family history is positive, and the typical presentation is short stature with lower extremity bowing. Muscle weakness is conspicuously mild or absent when the osteomalacia is due to X-linked hypophosphatemia.

Autosomal dominant hypophosphatemic rickets is characterized by a positive family history, spontaneous remissions, rather abrupt onset of profound fatigue and weakness, fractures, bone pain, and recurrent dental abscesses. This disorder may be triggered by iron deficiency from menorrhagia, nosebleeds, or pregnancy.

Hypocalcemia is usually mild to moderate but rarely can be severe enough to present with fingertip paresthesias, muscle cramps, or seizures, especially in patients with epilepsy. If the osteomalacia is mistaken for osteoporosis and treatment is started with a bisphosphonate or denosumab, the patient may experience new-onset paresthesias, muscle cramps, and palpitations. This not uncommon scenario occurs because the antiresorptive treatment interferes with the mobilization of calcium from bone by parathyroid hormone (PTH), thereby aggravating the hypocalcemia. The secondary hyperparathyroidism will also worsen the hypophosphatemia by the effect of PTH on renal excretion at the same time that intestinal absorption is impaired and mobilization from bone is blocked.